SECTION 2.5 CLINICAL OVERVIEW EMTRICITABINE/RILPIVIRINE

Transcription

SECTION 2.5
CLINICAL OVERVIEW
EMTRICITABINE/RILPIVIRINE/
TENOFOVIR DISOPROXIL FUMARATE
FIXED-DOSE COMBINATION
Gilead Sciences International Limited
18 August 2010
CONFIDENTIAL AND PROPRIETARY INFORMATION
Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate
Section 2.5 Clinical Overview
Final
TABLE OF CONTENTS
SECTION 2.5 CLINICAL OVERVIEW ...............................................................................................................1
TABLE OF CONTENTS .......................................................................................................................................2
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................7
2.5. CLINICAL OVERVIEW.............................................................................................................................12
2.5.1. Product Development Rationale .....................................................................................................12
2.5.1.1. Introduction and Background........................................................................................12
2.5.1.2. HIV-1 Infection and Current Approaches to Treatment................................................14
2.5.1.3. Rationale for Development of the FTC/RPV/TDF FDC Tablet....................................15
2.5.1.4. Overview of Clinical Development Program................................................................16
2.5.2. Overview of Biopharmaceutics.......................................................................................................18
2.5.2.1. Details of Formulation ..................................................................................................18
2.5.2.2. Results of Bioequivalence Study GS-US-264-0103......................................................20
2.5.2.3. Effect of Food ...............................................................................................................22
2.5.2.3.1.
Emtriva ....................................................................................................22
2.5.2.3.2.
Rilpivirine ................................................................................................23
2.5.2.3.3.
Viread ......................................................................................................24
2.5.2.3.4.
Truvada FDC tablet .................................................................................24
2.5.2.3.5.
FTC/RPV/TDF FDC tablet......................................................................24
2.5.3. Overview of Clinical Pharmacology...............................................................................................25
2.5.3.1. Pharmacology/Virology ................................................................................................25
2.5.3.1.1.
Mechanism of Action ..............................................................................25
2.5.3.2. Clinical Pharmacodynamics ..........................................................................................27
2.5.3.3. Clinical Pharmacokinetics.............................................................................................28
2.5.3.3.1.
Pharmacokinetic Profiles .........................................................................28
2.5.3.3.2.
Demographic Effects ...............................................................................32
2.5.3.3.3.
Renal Impairment ....................................................................................35
2.5.3.3.4.
Hepatic Impairment .................................................................................36
2.5.3.4. Potential for Drug Interactions ......................................................................................37
2.5.3.4.1.
Emtricitabine and Tenofovir DF..............................................................37
2.5.3.4.2.
Rilpivirine ................................................................................................38
2.5.3.4.3.
Clinically Important Drug Interactions ....................................................42
2.5.3.5. Summary of Clinical Pharmacology .............................................................................46
2.5.4. Overview of Efficacy ......................................................................................................................47
2.5.4.1. Efficacy of Emtricitabine ..............................................................................................48
2.5.4.2. Efficacy of Rilpivirine...................................................................................................48
2.5.4.3. Efficacy of Tenofovir DF..............................................................................................48
2.5.4.4. Efficacy of the Truvada FDC Tablet.............................................................................48
2.5.4.4.1.
Efficacy in Study GS-01-934...................................................................52
2.5.4.4.2.
Efficacy in Study GS-99-903...................................................................55
2.5.4.4.3.
Efficacy in Study M02-418......................................................................57
2.5.4.5. Efficacy of the FTC/RPV/TDF FDC Tablet .................................................................58
2.5.4.5.1.
Subanalysis of the Virologic Outcomes using Pooled
Data for Subjects Receiving RPV or EFV in
Combination with FTC/TDF ...................................................................62
2.5.4.5.2.
Baseline Genotype and Phenotype Characteristics ..................................63
2.5.4.5.3.
Efficacy in Studies C209 and C215 .........................................................65
2.5.4.6. Summary of Clinical Resistance Findings ....................................................................77
2.5.4.6.2.
Clinical Resistance Findings for C209 and C215 ....................................81
2.5.4.7. Conclusions on Resistance Determination ....................................................................91
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Conclusions on Resistance Determination for
Emtricitabine ...........................................................................................91
2.5.4.7.2.
Conclusions on Resistance Determination for
Rilpivirine ................................................................................................92
2.5.4.7.3.
Conclusions on Resistance Determination for Tenofovir
DF ............................................................................................................93
2.5.4.7.4.
Conclusions on Resistance Determination for the
FTC/RPV/TDF FDC Tablet.....................................................................93
2.5.4.8. Efficacy Against HBV in HIV/HBV Coinfected Subjects ............................................93
2.5.4.9. Efficacy Discussion and Conclusions ...........................................................................94
2.5.5. Overview of Safety .........................................................................................................................97
2.5.5.1. Introduction...................................................................................................................97
2.5.5.2. Summary of Clinical Trial Safety Experience...............................................................99
2.5.5.2.1.
Safety in Study GS-01-934 ......................................................................99
2.5.5.2.2.
Safety in Study GS-99-903 ....................................................................101
2.5.5.2.3.
Safety in Trials C209 and C215.............................................................103
2.5.5.2.4.
AE Data to Support the FTC/RPV/TDF FDC Tablet ............................121
2.5.5.3. Renal Adverse Events .................................................................................................125
2.5.5.3.1.
Renal Safety in Clinical Studies ............................................................125
2.5.5.3.2.
Experience in Postmarketing Surveillance ............................................128
2.5.5.3.3.
Mechanisms of Renal Toxicity ..............................................................129
2.5.5.3.4.
Risk Factors ...........................................................................................130
2.5.5.3.5.
Conclusions on Renal Safety .................................................................131
2.5.5.4. Effects on the Skin ......................................................................................................132
2.5.5.4.1.
Emtricitabine .........................................................................................132
2.5.5.4.2.
Rilpivirine ..............................................................................................132
2.5.5.4.3.
Tenofovir DF .........................................................................................134
2.5.5.4.4.
FTC/RPV/TDF FDC Tablet...................................................................134
2.5.5.5. Effects on the Bone .....................................................................................................134
2.5.5.5.1.
Emtricitabine .........................................................................................134
2.5.5.5.2.
Rilpivirine ..............................................................................................134
2.5.5.5.3.
Tenofovir DF .........................................................................................134
2.5.5.5.4.
2.5.5.6. Mitochondrial Toxicity and Metabolic Effects ...........................................................136
2.5.5.6.1.
Emtricitabine .........................................................................................137
2.5.5.6.2.
Rilpivirine ..............................................................................................137
2.5.5.6.3.
Tenofovir DF .........................................................................................138
2.5.5.6.4.
2.5.5.7. Neurologic Events.......................................................................................................140
2.5.5.7.1.
Emtricitabine .........................................................................................140
2.5.5.7.2.
Rilpivirine ..............................................................................................140
2.5.5.7.3.
Tenofovir DF .........................................................................................142
2.5.5.7.4.
2.5.5.8. Psychiatric Events .......................................................................................................143
2.5.5.8.1.
Emtricitabine .........................................................................................143
2.5.5.8.2.
Rilpivirine ..............................................................................................143
2.5.5.8.3.
Tenofovir DF .........................................................................................144
2.5.5.8.4.
2.5.5.9. Hepatic Events ............................................................................................................145
2.5.5.9.1.
Emtricitabine .........................................................................................145
2.5.5.9.2.
Rilpivirine ..............................................................................................145
2.5.5.9.3.
Tenofovir DF .........................................................................................146
2.5.5.9.4.
2.5.5.9.5.
Hepatitis B and/or C Coinfection...........................................................147
2.5.5.10. Events of Interest Potentially Related to QT Interval Prolongation ............................149
2.5.4.7.1.
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2.5.5.10.1. Emtricitabine .........................................................................................149
2.5.5.10.2. Rilpivirine ..............................................................................................149
2.5.5.10.3. Tenofovir DF .........................................................................................152
2.5.5.10.4. FTC/RPV/TDF FDC Tablet...................................................................152
2.5.5.11. Endocrine Events ........................................................................................................152
2.5.5.11.1. Emtricitabine .........................................................................................152
2.5.5.11.2. Rilpivirine ..............................................................................................152
2.5.5.11.3. Tenofovir DF .........................................................................................153
2.5.5.11.4. FTC/RPV/TDF FDC Tablet...................................................................153
2.5.5.12. Safety in Special Populations......................................................................................153
2.5.5.12.1. Safety in Pregnancy ...............................................................................153
2.5.5.12.2. Safety in Elderly Patients.......................................................................154
2.5.5.12.3. Safety in Children ..................................................................................155
2.5.5.12.4. Safety in Renal Impairment ...................................................................155
2.5.5.12.5. Safety in Hepatic Impairment and in Subjects with HIV
and HBV and/or HCV Coinfection........................................................156
2.5.5.13. Conclusions on Safety Experience ..............................................................................157
2.5.6. Benefits and Risks Conclusions ....................................................................................................162
2.5.7. References.....................................................................................................................................170
2.5.8. List of Gilead Nonclinical and Clinical Reports ...........................................................................184
LIST OF IN-TEXT TABLES
Table 1.
Table 2.
Table 3.
Table 4.
Table 5.
Table 6.
Table 7.
Table 8.
Table 9.
Table 10.
Table 11.
Table 12.
Table 13.
CONFIDENTIAL
GS-US-264-0103: Statistical Comparisons of FTC, TFV, and RPV
Pharmacokinetic Parameters for Test (Formulation 3) Versus
Reference Treatment ..............................................................................................................22
Steady-State Pharmacokinetics of TMC278 After Administration of
TMC278 25 mg Once Daily in Healthy Subjects (Trial C130 and
C152) and in HIV-1 Infected Subjects (Trials C209 and C215,
Pharmacokinetic Substudies) .................................................................................................32
Coadministration Recommendations Based on Drug-Drug Interaction
Trials or Predicted Interaction (Rilpivirine) ...........................................................................44
Principal Clinical Studies that Support Use of the Truvada Tablet –
Design and Population Characteristics...................................................................................50
GS-01-934: Treatment Outcomes at Week 48 (TLOVR Analysis)........................................52
GS-01-934: Treatment Outcomes at Week 144 (TLOVR Analysis,
Week 144 Efficacy Analysis Set)...........................................................................................53
GS-99-903: Summary of Response Rates of HIV-1 RNA 400 and
50 Copies/mL (ITT Population, Missing/Switch = Failure) ...............................................55
M02-418: Proportion of Subjects with HIV-1 RNA < 50 Copies/mL at
Weeks 48 and 96 ....................................................................................................................58
Principal Clinical Studies that Support Use of the FTC/RPV/TDF
FDC Tablet – Design and Population Characteristics ............................................................60
FTC/TDF Subset of the Pooled Phase 3 Trials C209 and C215:
Virologic and Immunological Outcomes of Randomized Treatment at
Week 48 (TLOVR Analysis)..................................................................................................62
Rilpivirine Studies C209 and C215 (Pooled Data for Subjects
Receiving RPV or EFV in Combination with FTC/TDF): Virologic
Outcome of Randomized Treatment at Week 48 (Snapshot Analysis) ..................................63
Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Virologic
Outcome (< 50 HIV-1 RNA Copies/mL, Snapshot) at Week 48 ...........................................68
Rilpivirine Studies C209 and C215 (Pooled Data): Proportion of
Virologic Responders (< 50 HIV-1 RNA Copies/mL, TLOVR) at
Week 48 by Subgroups ..........................................................................................................72
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Table 14.
Table 15.
Table 16.
Table 17.
Table 18.
Table 19.
Table 20.
Table 21.
Table 22.
Table 23.
Table 24.
Table 25.
Table 26.
Table 27.
Table 28.
Table 29.
Table 30.
Table 31.
Table 32.
Final
GS-01-934: Cumulative Development of Resistance by Week 144 ......................................80
Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures Number of Treatment-Emergent Reverse Transcriptase Mutations at
Failure ....................................................................................................................................84
Rilpivirine Studies C209 and C215 (Pooled Data): Virologic Failures:
Individual Treatment-Emergent Resistance-Associated Mutations by
Type at Failure in at Least 2 Subjects from the Pooled TMC278 or
Control Group ........................................................................................................................85
Virologic Failures: Number of Treatment-Emergent Mutations Failure ....................................................................................................................................87
Virologic Failures: Emergent Extended NNRTI Mutations, IAS USA
NNRTI Mutations and IAS-USA N(t)RTI Mutations - Failure .............................................88
Virologic Failures: Phenotypic Resistance – Failure .............................................................91
Estimated Cumulative Postmarketing Exposure to the Individual
Marketed Products .................................................................................................................98
GS-01-934: Treatment-Emergent Adverse Events Reported in at Least
10% of Subjects in Either Treatment Group (Safety Analysis Set)......................................100
Rilpivirine Studies C209 and C215: Summary of Adverse Events
(Phase 3 Week 48 Analysis).................................................................................................105
Rilpivirine Studies C209 and C215: Lipid Values Reported in Subjects
Receiving RPV or EFV in Combination with FTC/TDF .....................................................117
Rilpivirine Studies C209 and C215: Treatment-Emergent Abnormal
Cortisol Response to ACTH Stimulation (Worst Case) (Phase 3 Week
48 Pooled Analysis) .............................................................................................................119
Tabulated Summary of Adverse Reactions Associated with the
Individual Components of the FTC/RPV/TDF FDC Tablet Based on
Clinical Study and Postmarketing Experience .....................................................................122
Summary of Gilead Clinical Studies that Assessed Renal Safety in
HIV-1 Infected Subjects Receiving TDF .............................................................................126
Rilpivirine Trials C209 and C215: Treatment-Related Rash (Grouped
Term) Summary (Phase 3 Week 48 Pooled Analysis) .........................................................133
Rilpivirine Trials C209 and C215: Neurologic Events of Interest
Summary (Phase 3 Week 48 Pooled Analysis) ....................................................................141
Rilpivirine Trials C209 and C215: Neurologic Events of Interest in at
Least 1.0% of Subjects in the TMC278 or Control Group, Regardless
of Severity and Causality (Phase 3 Week 48 Pooled Analysis) ...........................................142
Rilpivirine Studies C209 and C215: Psychiatric Events of Interest in at
Least 1.0% of Subjects in the TMC278 or Control Group, Regardless
of Severity and Causality (Phase 3 Week 48 Pooled Analysis) ...........................................144
Gilead Nonclinical Reports ..................................................................................................185
Gilead Clinical Reports ........................................................................................................221
LIST OF IN-TEXT FIGURES
Figure 1.
Figure 2.
Figure 3.
CONFIDENTIAL
GS-01-934: Mean (95% CI) Change from Baseline in HIV-1 RNA by
Study Visit (AT Analysis Set)................................................................................................54
GS-01-934: Mean (95% CI) Change From Baseline in CD4 Cell
Count (AT Analysis Set) ........................................................................................................54
GS-99-903: Mean (95% CI) Change from Baseline in Plasma HIV-1
RNA Levels (ITT Analysis Set).............................................................................................56
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Figure 4.
Figure 5.
Figure 6.
Figure 7.
Figure 8.
Figure 9.
Figure 10.
Figure 11.
CONFIDENTIAL
Final
GS-99-903: Mean (95% CI) Change from Baseline in CD4 Cell Count
(ITT Analysis Set)..................................................................................................................56
Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials: Proportion
of Virologic Responders (< 50 HIV-1 RNA copies/mL, TLOVR) at
Week 48 .................................................................................................................................66
Rilpivirine Studies C209 and C215: Statistical Comparisons of
Adverse Events Regardless of Relationship to Investigational
Medication - Grouped terms (Phase 3 Week 48 Pooled Analysis).......................................107
Medication – Most Frequent (> 10% overall) Individual Preferred
Terms (Phase 3 Week 48 Pooled Analysis) .........................................................................108
Rilpivirine Studies C209 and C215: Mean Change (r95% CI) from
Baseline in Hemoglobin by Background Regimen: FTC/TDF (Top);
AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled
Analysis) ..............................................................................................................................111
Baseline in Creatinine by Background Regimen: FTC/TDF (Top);
AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48 Pooled
Analysis of C209 and C215) ................................................................................................113
Baseline in Total Cholesterol, HDL Cholesterol, Total
Cholesterol/HDL Cholesterol Ratio, LDL Cholesterol and
Triglycerides Over Time (Fasted) (Phase 3 Week 48 Pooled Analysis) ..............................115
Baseline in QTcF interval Over Time: Overall (top) and Subanalysis
by Gender (Phase 3 Week 48 Pooled Analysis) ...................................................................150
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
3TC
lamivudine
ABC
abacavir
ACTG
AIDS Clinical Trials Group
ACTH
adrenocorticotropic hormone
ADR
adverse drug reactions
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
AUC24h
area under the plasma/serum concentration versus time curve from time 0 to
24 hours after dosing
AUCinf
area under the concentration versus time curve extrapolated to infinite time,
calculated as AUC0last + (Clast/Oz)
AUClast
area under the concentration versus time curve from time zero to the last
quantifiable concentration
AUCtau
area under the concentration versus time curve over the dosing interval
AVMR
antiviral microbiology report
AZT
zidovudine; ZDV
BCO
biological cut-off
BID
twice daily
BMD
bone mineral density
Caco-2
colon carcinoma-derived
CBV
Combivir (lamivudine/zidovudine)
CCO
clinical cut-off
CDC
Center for Disease Control and Prevention
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CLcr
creatinine clearance
CL/F
apparent clearance
Cmax
maximum observed concentration of drug in plasma
Cmin
minimum observed concentration of drug in plasma (trough level)
CPT
Child-Pugh-Turcotte (classification system for hepatic impairment)
CRR or CSR
clinical research report or study report
CV
coefficient of variation
CYP
cytochrome P450
d4T
stavudine
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
dATP
deoxyadenosine triphosphate
dCTP
deoxycytidine triphosphate
ddI
didanosine
DHEAS
dehydroepiandrosterone sulphate
DHHS
Department of Human Health and Services
DNA
deoxyribonucleic acid
DLV
delavirdine
DRV
darunavir
EACS
European AIDS Clinical Society
EC
enteric coated
EC50
median 50% effective concentration
ECG
electrocardiogram
EFV
efavirenz (Sustiva)
eGFR
estimated glomerular filtration rate
eGFRcreat
estimated glomerular filtration rate for creatinine as calculated by modification of
diet in renal disease (MDRD) formula
eGFRcyst
estimated glomerular filtration rate for cystatin C
EMA, EMEA
European Medicines Agency
EOI
event of interest
ESRD
end-stage renal disease
ETR
etravirine
EU
European Union
FC
fold change
FDA
(US) Food and Drug Administration
FDC
fixed-dose combination
FTC
emtricitabine (Emtriva)
FTC/RPV/TDF
emtricitabine/rilpivirine/tenofovir disoproxil fumarate (fixed-dose combination
product)
FTC/TDF
emtricitabine/tenofovir disoproxil fumarate (Truvada; fixed-dose combination
product)
FTC-TP
emtricitabine triphosphate
GAM
generalized additive models
GFR
glomerular filtration rate
GLS
geometric least squares
H2
histamine-2
HAART
highly active antiretroviral therapy
HBV
hepatitis B virus
HCV
hepatitis C virus
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HDL
high-density lipoprotein
HIV-1 (-2)
human immunodeficiency virus type 1 (-2)
hOAT (1, 3)
human organic anion transporter (type 1, type 3)
HOMA-IR
homeostasis model assessment insulin resistance
HPLC
high-performance liquid chromatography
IAS-USA
International AIDS Society-United States of America
ICH
International Conference on Harmonization
IC50
50% inhibitory concentration
IDV
indinavir
ITT
intent-to-treat
Ki
inhibition constant
LDL
low-density lipoprotein
LOCF
last observation carried forward
LPV
lopinavir
LPV/r
lopinavir/ritonavir
M=F
missing = failure
MAA
(EU) Marketing Authorization Application
MCS
mental component summary
MDCK
Madin-Darby canine kidney
MDRD
modification of diet in renal disease
MITT
modified intent-to-treat
MRP (2,4)
multidrug resistance protein (type 2, type 4)
mtDNA
mitochondrial DNA
NC = F
noncompleter = failure
NNRTI
nonnucleoside reverse transcriptase inhibitor
non-VF
non-virologic failure
NRTI
nucleoside reverse transcriptase inhibitor
NtRTI, N(t)RTI
nucleotide reverse transcriptase inhibitor
NVP
nevirapine
PBMC
peripheral blood mononuclear cell
PCS
Physical Component Summary
P-gp
P-glycoprotein
PI
protease inhibitor
PK
pharmacokinetic
PMPA
9-R-2-(phosphonomethoxy)propyl]adenine
PP
per protocol
PNP
purine nucleoside phosphorylase
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PSUR
periodic safety update report
QT
interval representing the time for both ventricular depolarization and repolarization
to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected by Fridericia’s formula
/r
ritonavir boosted
RAM
resistance-associated mutation
RNA
ribonucleic acid
RPTEC
renal proximal tubule cell
RPV
rilpivirine (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV)
RT
reverse transcriptase
RTV
ritonavir (Norvir)
rtv
coadministered low-dose ritonavir
SAE
serious adverse event
SAWP
Scientific Advice Working Party
SD
SF-36v2
standard deviation

Short Form-36 version 2
SmPC
Summary of Product Characteristics
SNPs
single-nucleotide polymorphisms
SOC
system organ class
T½, t1/2, term
terminal elimination half-life
TAM
thymidine analogue-associated mutation
Tenofovir DF, TDF
tenofovir disoproxil fumarate (Viread), (300 mg TDF is equivalent to 245 mg
tenofovir disoproxil or 136 mg of tenofovir)
TFV
tenofovir
TLOVR
time to loss of virologic response
TMC
Tibotec Medicinal Compound
tmax
time (observed time point) of Cmax
TQT
thorough QT
US, USA
United States
VF
virologic failure
ZDV
zidovudine; AZT
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Rilpivirine Trial Naming Conventions
Throughout the development of TMC278, several different naming conventions were used
for trials. The first part of the trial identifier was one of the following, depending on when the
trial was conducted:
x
R278474-CDE- (used for the earlier trials)
x
R278474-
x
TMC278-
x
TMC278-TiDP6- (used for the most recent trials)
All trials were given a suffix of a unique 3-digit number preceded by the letter C (for
“clinical”), e.g., C215 or C209. In this document, trials are referred to by only the final
4 characters of the trial identifier (e.g., C209, C215).
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2.5.
CLINICAL OVERVIEW
2.5.1.
Product Development Rationale
2.5.1.1.
Introduction and Background
Final
This dossier is being submitted in support of a marketing authorization application (MAA)
for a fixed-dose combination (FDC) film-coated tablet that contains the active substances
emtricitabine (FTC), rilpivirine (RPV, which is also referred to as TMC278 throughout this
document), and tenofovir disoproxil fumarate (tenofovir DF, TDF). This FDC tablet is
referred to as emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF)
throughout this document. Each FTC/RPV/TDF FDC tablet contains FTC, RPV, and TDF at
the same dosages as recommended for the individual components in adults, i.e., 200 mg of
FTC, 25 mg RPV (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV), and
300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil or 136 mg tenofovir [TFV]).
Individual presentations of FTC (Emtriva) and TDF (Viread) are currently approved in the
United States (US), the European Community, and other countries worldwide for use in
adults. It is proposed that FTC/RPV/TDF FDC tablets be indicated for the treatment of
HIV-1 infection in adults and taken orally once daily with a meal.
Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a synthetic analog of
the naturally occurring pyrimidine nucleoside, 2ƍ-deoxycytidine. Intracellularly, FTC is
phosphorylated by cellular enzymes to form emtricitabine triphosphate (FTC-TP), the active
metabolite. Emtricitabine is the active ingredient in Emtriva hard capsules and oral solution.
The Committee for Medicinal Products for Human Use (CHMP) approved Emtriva for the
treatment of human immunodeficiency virus type 1 (HIV-1) infection on 24 October 2003
(EU/1/03/261/001-003).
Rilpivirine, which is developed by Tibotec BVBA, is an investigational agent of the
nonnucleoside reverse transcriptase inhibitor (NNRTI) class that shows in vitro activity
against wild-type HIV-1 and against HIV-1 strains harboring different mutations that result
in resistance to the first-generation NNRTIs. Tibotec BVBA will submit their MAA in
accordance with Article 8.3 of Directive 2001/83/EC.
Tenofovir DF, the oral prodrug of TFV, is a nucleotide reverse transcriptase inhibitor
(NtRTI). After absorption, TDF is rapidly converted to TFV, which is metabolized
intracellularly to the active metabolite, tenofovir diphosphate. Tenofovir disoproxil (as
fumarate) is the active ingredient in Viread 300-mg film-coated tablets. The CHMP approved
Viread for the treatment of HIV-1 infection on 05 February 2002, (EU/1/01/200/001-2).
Truvada film-coated tablets are an FDC containing 200 mg of FTC and 300 mg of TDF.
The CHMP approved Truvada for the treatment of HIV-1 infection on 21 February 2005
(EU/1/04/305/001).
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Atripla film-coated tablets (EFV/FTC/TDF) are an FDC containing 600 mg of efavirenz
(EFV), which is an NNRTI, 200 mg of FTC, and 300 mg of TDF. The CHMP approved
Atripla for the treatment of HIV-1 infection on 13 December 2007 (EU/1/07/430/001-2).
In some regions, Emtriva and Viread are approved for use in adolescents; Emtriva, which is
also available as an oral solution formulation, may be administered to children as young as
4 months of age.
A comprehensive program of clinical studies with FTC, TDF, and Truvada has previously
been submitted in the original MAAs for Emtriva 200-mg hard capsules and Emtriva
10-mg/mL oral solution; Viread 300-mg film-coated tablets; and Truvada film-coated tablets.
In addition, a variety of supplementary information from clinical studies with FTC, TDF, and
Truvada has been submitted postauthorization, either via variations to the original marketing
authorization or in accordance with specific obligations, follow-up measures, and periodic
safety update reports for the above-mentioned products, as appropriate.
In accordance with the advice received from the European Medicines Agency (EMA) at the
meeting held on
20 (see Module 1.2.5.14,
meeting minutes) and in accordance with the Committee for Proprietary
Medicinal Products Guideline on Fixed Combination Medicinal Products
(CPMP/EWP/240/95 Rev. 1, 21 February 2008), the present application for a marketing
authorization is being submitted in accordance with Article 8.3 of Directive 2001/83/EEC, as
amended. The MAAs for RPV as a single agent tablet and for the FTC/RPV/TDF FDC tablet
are being submitted in parallel by Tibotec BVBA and Gilead Sciences, respectively.
As the RPV component is a new chemical entity, this FDC MAA dossier contains full data
on this new component while providing the key data on the Truvada (i.e., FTC, TDF, and
FTC/TDF) components that support the efficacy and safety claims in the FTC/RPV/TDF
FDC prescribing information. All Truvada studies considered to support the FDC are
included to ensure that this is a “stand-alone dossier.” This is in agreement with the feedback
received at the
meeting with the EMA on
20 and with the meeting
with
on
20 (see Module 1.2.5.14, final minutes). To assist the
reviewer, a listing of all the FTC, TDF, FTC/TDF, and EFV/FTC/TDF nonclinical and
clinical reports is provided in Section 2.5.8. Clinical data for FTC, RPV, TDF, Truvada, and
Atripla are provided in Module 2.7; clinical study reports (CSRs), periodic safety update
reports (PSURs) and other relevant data for these products are provided in Module 5.
On
20 , Tibotec BVBA sought scientific advice for RPV and FDC tablets
containing RPV (EMEA/CHMP/SAWP/670243/2009 corrigendum, see Module 1.2.5.14,
Scientific Advice). The Scientific Advice Working Party (SAWP) confirmed that the
demonstration of bioequivalence would be mandatory and should take into account the
influence of food, but an additional specific clinical study to support the FTC/RPV/TDF FDC
would not be needed, given the available clinical data on the combined use of the FDC
components. The pharmacokinetic, efficacy, and safety data will characterize the benefits and
risks of the component products in HIV-1 infected adult subjects; however, apart from
bioequivalence studies conducted in the fed state, no clinical studies have been conducted
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with the FTC/RPV/TDF FDC. The 2 registrational trials for RPV, TMC278-TiDP6-C209
(C209, also known as ECHO) and TMC278-TiDP6-C215 (C215, also known as THRIVE),
included Truvada as backbone antiretroviral therapy for approximately 80% of subjects in the
pooled analysis.
This overview presents the clinical rationale for the development of the FTC/RPV/TDF FDC
and reviews the information that is relevant to the assessment of the FTC/RPV/TDF FDC.
This information includes the bioequivalence data and the clinical efficacy and safety data
that support the positive benefit:risk profile for the use of the FTC/RPV/TDF FDC tablet for
treatment of HIV-1 infection in adults. Justification is provided for specific recommendations
for the use of the FTC/RPV/TDF tablet, as described in the proposed FTC/RPV/TDF
prescribing information.
2.5.1.2.
HIV-1 Infection and Current Approaches to Treatment
HIV-1 infection is a life-threatening and serious disease that is of major public health interest
worldwide. There are now approximately 33 million people worldwide living with HIV-1
{12896}. The infection, if left untreated or suboptimally treated, is characterized by
deterioration in immune function, the subsequent occurrence of opportunistic infections and
malignancies, and death. Therapeutic strategies for the treatment of HIV-1 disease have been
significantly advanced by the availability of highly active antiretroviral therapy (HAART),
and the introduction of HAART was associated with a dramatic fall in acquired
immunodeficiency syndrome (AIDS)-related mortality and morbidity in the US and Europe
{2537}, {5125}, {8284}.
The goal of antiretroviral therapy for HIV-1 infection is to delay disease progression and
increase the duration of survival by achieving maximal and prolonged suppression of HIV-1
replication. The standard of care for treatment involves the use of a combination of
antiretroviral agents, typically a combination of at least 3 drugs, including a NNRTI or a
protease inhibitor (PI) and 2 agents from the NRTI/NtRTI class.
NNRTIs play an important role and are widely used in the treatment of HIV-1 infection, most
commonly in first line therapy. The currently approved NNRTIs in the US and/or Europe for
use in treatment-naive adult patients are nevirapine (NVP; Viramune) {15969}, delavirdine
(DLV; Rescriptor) {15967}, and EFV {15807}. These NNRTIs can be associated with
safety and tolerability concerns (mainly hepatotoxicity, central nervous system symptoms,
rash, and/or the risk of teratogenicity {15207}. Currently one novel NNRTI, etravirine (ETR,
Intelence), developed by Tibotec BVBA, is approved for use only in HIV-1 infected,
treatment-experienced adult patients.
In recent years, new antiretroviral therapies have been approved with improved safety
profiles and convenient dosing regimens. However, from results of controlled clinical trials,
it is apparent that not all regimens are equivalent in terms of potency or toxicity. International
treatment guidelines list FTC and TDF as a preferred NRTI/NtRTI backbone in an
antiretroviral regimen for initial therapy {15207}, {12716}, {14065}.
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Although HAART has dramatically improved the prognosis of patients infected with HIV-1,
eradication of the virus is not possible with therapies that are currently available. To achieve
successful long-term treatment, maximizing viral suppression and prevention of drug
resistance have become the primary goals. Adherence is known to be paramount in
maintaining viral suppression, as missing doses can result in viral rebound and increased risk
of resistance development. Among regimens of comparable efficacy, both physicians and
HIV-1 infected patients receiving antiretroviral therapy rate total pill burden, dosing
frequency, and safety concerns among the greatest obstacles to achieving adherence {4266},
{4256}.
Thus, there continues to be a need for new treatments that combine potent and sustained
efficacy with acceptable tolerability and minimal long-term toxicity, as well as practical and
convenient dosing.
2.5.1.3.
Rationale for Development of the FTC/RPV/TDF FDC Tablet
The FTC/RPV/TDF fixed-dose combination tablet represents a new complete regimen for
administration as a single tablet, to be taken once daily with a meal, for the treatment of
adults with HIV-1 infection.
Current treatment guidelines recommend that initial therapy for HIV-1 infected subjects
should consist of HAART: 2 NRTIs such as Truvada (FTC/TDF), plus either a NNRTI,
usually EFV, or a ritonavir (RTV)-boosted protease inhibitor {12716}, {14065}, {15207}.
While combination antiretroviral therapy has been largely successful in reducing the
morbidity and mortality associated with HIV disease, a significant proportion of patients
eventually experience loss of virologic, immunologic, or clinical benefit from their current
regimens. Also, a significant proportion of patients experience side effects that can lead to
poor/incomplete regimen adherence and missed doses that can result in loss of virologic,
immunologic, or clinical benefit.
Incomplete adherence to antiretroviral regimens is a critical factor contributing to the
development of viral resistance and treatment failure, and is thus a primary barrier to
successful long-term treatment. Clinical studies have clearly demonstrated high levels of
adherence and treatment satisfaction with simple, once-daily HAART regimens, resulting in
persistent suppression of HIV viral load {7034}, {7035}, {7036}. Currently, Atripla
represents the only simplified one tablet, once-daily product for the treatment of HIV-1.
Gilead Sciences has coformulated RPV, a potent NNRTI, with the standard-of-care NRTI
backbone FTC/TDF into an FDC tablet to be administered once daily with a meal. This FDC
represents a significant benefit to HIV-1 infected patients due to simplified dosing. The FDC
of FTC/RPV/TDF has the potential to combine a next generation NNRTI, having an
improved safety profile compared to EFV, with the standard-of-care, preferred-agent
NRTIs FTC and TDF. This fixed-dose regimen would potentially be the second highly
active, once daily FDC regimen, and will address limitations with the only other fixed-dose
regimen (EFV/FTC/TDF). The combination tablet of FTC/RPV/TDF offers an attractive
treatment option to a significant number of patients who wish to avoid using EFV due to
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concerns about tolerability (including central nervous system adverse reactions) and its
potential for teratogenicity. Therefore, there remains a need for new combinations of potent
agents exhibiting favorable tolerability, minimal short and long-term toxicity, and convenient
dosing to maximize patient adherence.
2.5.1.4.
Overview of Clinical Development Program
Emtricitabine and TDF underwent extensive development programs. The clinical trial
programs of these agents were designed in accordance with regulatory guidance and clinical
practice recommendations available at the time. The safety profiles of FTC, TDF, Truvada,
and Atripla continue to be monitored through postmarketing surveillance and are reviewed in
PSURs. Data from the clinical program on RPV are being submitted to the EMA both within
this MAA and in the parallel submission for RPV.
The basis of the MAA for the FTC/RPV/TDF FDC tablet for the treatment of HIV-1
infection in adults is described in Section 2.5.1.1. The application is supported by data from
Study GS-US-264-0103, which establishes bioequivalence between the FDC tablet and the
concurrent administration of the individual agents. The data that support bioequivalence are
described in Section 2.5.2.2. Additionally, data are reviewed from the comparative Phase 3
clinical studies C209 and C215 that provide efficacy and safety data most relevant to the use
of the FTC/RPV/TDF FDC tablet.
x
Study C209 (also known as ECHO) is an ongoing double-blind, double-dummy activecontrolled Phase 3 study to investigate the long-term efficacy, safety, and tolerability of
TMC278 25 mg once daily compared with EFV 600 mg once daily (control), each in
combination with a background regimen containing TDF and FTC. It is being conducted
in USA, Canada, Europe, Australia, Asia, Africa, and Latin America. The key efficacy
and safety data were obtained from the Week 48 primary analyses of this study. The
analyses were performed when all subjects had completed at least 48 weeks of treatment
or had discontinued earlier (i.e., up to the cut-off date of 01 February 2010) (see
Module 5.3.5.1, TMC278-C209 clinical research report [CRR]).
x
Study C215 (also known as THRIVE) is an ongoing double-blind, double-dummy activecontrolled Phase 3 study to investigate the long-term efficacy, safety and tolerability of
TMC278 25 mg once daily compared with EFV 600 mg once daily (control). Each of
these nonnucleoside reverse transcriptase inhibitors (NNRTIs) was given in combination
with a background regimen containing 2 nucleoside/nucleotide reverse transcriptase
inhibitors (N[t]RTIs). It is also being conducted in USA, Canada, Europe, Australia,
Asia, Africa, and Latin America. The key efficacy and safety data were obtained from the
Week 48 primary analyses of this study. The analyses were performed when all subjects
had completed at least 48 weeks of treatment or had discontinued earlier (i.e., up to the
cut-off date of 28 January 2010) (see Module 5.3.5.1, TMC278-C215 CRR).
The combination antiretroviral (ARV) treatment in the Phase 3 trials is in line with current
treatment guidelines for HIV-1 infected, treatment-naive patients {15207}, {15965}. In
C209, subjects received a fixed background regimen consisting of FTC/TDF. In C215, the
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background regimen contained 2 investigator-selected N(t)RTIs: either abacavir [ABC]/3TC,
zidovudine [AZT]/3TC, or FTC/TDF. The background N(t)RTIs were to be fully active on
screening resistance tests so as to maximize the potential for initial treatment response.
These 2 ongoing Phase 3 trials also form the basis of the TMC278 MAA.
Further comprehensive data from the 96-week efficacy and safety analysis of the
dose-finding Phase 2b trial (TMC278-C204 [C204]) and long-term data up to 192 weeks of
that same trial also support the FTC/RPV/TDF FDC MAA (see Modules 2.7.3 and 2.7.4 for
Phase 2b data). In addition, a study with TMC278 was conducted in approximately
40 treatment-experienced HIV-1 infected subjects (Module 2.7.3.2.2.3.2 and
Module 5.3.5.2, R27874-C202 CRR).
The use of the FTC/TDF tablet is primarily supported by efficacy and safety data from the
following principal studies:
x
GS-01-934 is a completed, Phase 3, 288-week, open-label study, in which the once-daily
regimen of FTC, TDF, and EFV (administered as the individual products
[FTC + TDF + EFV] for the first 96 weeks and subsequently as the fixed-dose
combination of FTC/TDF (Truvada) and EFV [FTC/TDF + EFV] through 144 weeks) is
compared with the fixed-dose combination of Combivir (lamivudine/zidovudine, CBV)
administered twice daily and efavirenz once daily (CBV + EFV). After completing 144
weeks of treatment, subjects from both treatment groups switched to a once-daily
regimen of FTC, TDF, and EFV (as the Atripla tablet) in a 96-week extension period
(144 weeks at sites in EU countries where Atripla was not launched) (see Module 5.3.5.1,
GS-01-934 CSR).
x
GS-99-903 is an ongoing, Phase 3, 624-week study, in which the regimen of
TDF + 3TC + EFV was compared with a regimen of stavudine (d4T) + 3TC + EFV in a
double-blinded fashion for the first 144 weeks; from Week 144 to Week 480, patients at
selected sites received open-label TDF + 3TC + EFV; from Weeks 480 to 624 the
regimen of TDF + 3TC + EFV changed to open-label FTC/TDF (Truvada) + EFV. The
experience with the TDF + 3TC + EFV regimen in this study is relevant to the efficacy of
the Truvada tablet because (a) 3TC is a cytidine analog that is structurally closely related
to FTC; (b) the resistance profiles of 3TC and FTC, characterized by M184V/I
development, are similar; and (c) in Study FTC-303, FTC demonstrated equivalent
antiviral efficacy and safety to 3TC when each was administered in a triple combination
regimen to stable, treatment-experienced subjects (see Module 5.3.5.1, GS-01-903 CSR) .
x
M02-418 was a Phase 3, open-label, randomized, multicenter study in which
antiretroviral-naive, HIV-1 infected subjects received FTC and TDF once daily in
combination with a PI (800 mg/200 mg lopinavir/ritonavir (LPV/r) once daily or
400 mg/100 mg LPV/r twice daily) (see Module 5.3.5.1, M02-418 CSR).
No new supportive clinical efficacy and safety studies in subjects were considered warranted
on the basis of available safety data and extensive clinical experience with the use of FTC
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and TDF, both alone and in combination, and with RPV for the treatment of HIV-1 infection
in adults. The Scientific Advice Working Party confirmed that the demonstration of
bioequivalence would be mandatory and should take into account the influence of food, but
an additional specific clinical study to support the FTC/RPV/TDF FDC would not be needed,
given the available clinical data on the combined use of the FDC components (see
Module 1.2.5.14, Scientific Advice).
2.5.2.
Overview of Biopharmaceutics
For detailed information on the biopharmaceutic data described in this section, refer to
Module 2.7.1.
Information on bioavailability and the effect of food following oral administration of the
individual agents is provided in the proposed FTC/RPV/TDF FDC tablet prescribing
information.
This application for the FTC/RPV/TDF FDC tablet is supported by the bioequivalence study,
GS-US-264-0103, which was conducted in healthy volunteers to evaluate the bioequivalence
of 2 formulations of the FTC/RPV/TDF FDC tablet compared with a 200-mg capsule of
FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF taken concurrently under fed
conditions (see Section 2.5.2.2).
In the bioequivalence study, the pharmacokinetic equivalence of the 2 treatment
administrations (FTC/RPV/TDF FDC tablet [test] and concurrent administration of the
individual dosage forms [reference]) was determined by measures of the rate and extent of
absorption and systemic exposure (AUCinf, AUClast, and Cmax) for each agent. In accordance
with the Committee for Proprietary Medicinal Products Note for Guidance on the
Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1, 20 January 2010) and
FDA Guidance for Industry (Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products—General Considerations. March 2003), formulation
bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of geometric
least squares (GLS) means (test/reference) fell within 80% to 125% for the 3 primary
pharmacokinetic parameters (AUCinf, AUClast, and Cmax) for all analytes.
2.5.2.1.
Details of Formulation
For the FTC/RPV/TDF FDC, a series of formulation experiments were performed to identify
the appropriate composition that would allow the coformulation of the 3 active ingredients
into a single tablet. Four formulations of the FDC tablets were tested in 2 Phase 1 studies.
Formulations 1 and 2 FDC tablets were evaluated in Study GS-US-264-0101 (see
Module 5.3.1.2, GS-US-264-0101 CSR) and Formulations 3 and 4 FDC tablets were
evaluated in Study GS-US-264-0103 (see Module 5.3.1.2, GS-US-264-0103 CSR). In both
studies, all treatments were administered in the fed state.
The initial approach involved developing a dry cogranulation of FTC, RPV, and TDF and
compressing the blend into a single layer tablet (Formulation 1). Formulation 1 was
manufactured by blending the 3 active ingredients together with excipients then granulating
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together in a dry granulation process consisting of roller compaction and milling. The
granules were blended with extragranular excipients and compressed into tablet cores, which
were then film-coated. This process allowed for high manufacturing throughput with an
excellent yield.
The second approach consisted of 2 separate granulation processes in which RPV was wet
granulated by a fluid bed granulation process and FTC and TDF were cogranulated in a
high-shear wet granulation process. This formulation was designed to use the intragranular
RPV formulation and fluid-bed granulation process from the 25-mg RPV Phase 3 tablet. The
FTC/TDF powder blend was produced by the identical manufacturing process for Truvada
tablets and was the identical intragranular composition of Truvada tablets. The 2 granulations
were then blended together with lubricant, and compressed into a single layer tablet
(Formulation 2).
Formulations 1 and 2 failed to demonstrate bioequivalence in Study GS-US-264-0101 for
RPV, which had significantly higher area under the curve (AUC) and Cmax levels than those
obtained with the 25-mg RPV Phase 3 clinical formulation (the proposed commercial
formulation). These findings demonstrated the potential for physicochemical interactions
between RPV and FTC/TDF compressed as a single layer tablet formulation. Emtricitabine
and TFV AUC and Cmax levels from Formulations 1 and 2 were bioequivalent to the
commercial formulations of Emtriva capsules and Viread tablets, respectively.
Bilayer formulations with one layer containing RPV and the other layer containing FTC and
TDF were developed to minimize any potential physicochemical interactions between RPV
with FTC and TDF. The bilayer formulation approach involved 2 separate granulation
processes in which RPV was wet granulated by a fluid-bed granulation process, and FTC and
TDF were cogranulated in a high-shear wet granulation process. The 2 granulations were
physically separated by compressing the 2 blends into a bilayer tablet (Formulations 3 and 4).
While Formulations 3 and 4 utilized the same manufacturing process, the formulation
composition of the RPV granulation in each of the formulations differed in the relative
proportion of the excipients used (see Module 2.7.1.4.2 for quantitative compositions).
Formulations 3 and 4 were evaluated in Study GS-US-264-0103. Results from this study
demonstrated that exposure of FTC, RPV, and TDV, as assessed by AUCinf, AUClast, and
Cmax, were bioequivalent between Formulation 3 (test) and the individual components
(reference). Formulation 4 was found not to be bioequivalent with concurrent administration
of the individual components (see Modules 2.7.1.3.5.2 and 3.2.P.2.2).
The proposed commercial formulation of the FTC/RPV/TDF FDC tablet, Formulation 3, is a
purplish-pink, capsule-shaped, film-coated tablet, debossed with “GSI” on one side and
plain-faced on the other side, and containing 200 mg of FTC, 25 mg of RPV, and 300 mg of
TDF.
The FTC/RPV/TDF FDC tablet is a bilayer tablet with one layer containing RPV and the
other layer containing FTC and TDF. Each tablet contains the following inactive ingredients:
croscarmellose sodium, lactose monohydrate, povidone, polysorbate 20, magnesium stearate,
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pregelatinized starch, and microcrystalline cellulose. The quantitative composition of the
FTC/RPV/TDF tablet is summarized in Module 2.7.1.4.1.
Dissolution Profile
The FTC/RPV/TDF FDC tablets are an immediate-release, solid oral-dosage form. The
dissolution profiles for the proposed commercial tablet formulation (Lot BY1001B) showed
that greater than 80% of FTC and TDF dissolved within 30 minutes, while greater than 80%
of RPV dissolved in 60 minutes (see Module 2.7.1.1.2).
2.5.2.2.
Results of Bioequivalence Study GS-US-264-0103
Study GS-US-264-0103 was an open-label, randomized, 3-way crossover, pharmacokinetic
study in healthy subjects, designed to evaluate the bioequivalence of 2 distinct formulations
of the FTC/RPV/TDF FDC tablets (Formulations 3 and 4) compared with FTC, RPV, and
TDF taken concurrently under fed conditions. An earlier bioequivalence study,
GS-US-264-0101, evaluated the bioequivalence of 2 FDC tablet formulations
(Formulations 1 and 2). Although these formulations were not bioequivalent, the study report
for GS-US-264-0101 is included in Module 5. These studies are described in detail in
Modules 2.7.1.2.5.1 (GS-US-264-0103) and 2.7.1.2.5.2 (GS-US-264-0101).
The treatments used in Study GS-US-264-0103 were as follows:
FTC + RPV + TDF (reference): A single dose of FTC 1 u 200-mg strength capsule, RPV
1 u 25-mg strength tablet, and TDF 1 u 300-mg strength tablet administered together in the
morning and within 5 minutes of consuming a standardized meal
FTC/RPV/TDF FDC Formulation 3 (test): A single dose of FDC tablet (FTC 200 mg, RPV
25 mg [as 27.5 mg of the hydrochloride salt], and TDF 300 mg) administered in the morning
and within 5 minutes of consuming a standardized meal
FTC/RPV/TDF FDC Formulation 4 (test): A single dose of FDC tablet (FTC 200 mg, RPV
25 mg [as 27.5 mg of the hydrochloride salt], and TDF 300 mg) administered in the morning
and within 5 minutes of consuming a standardized meal
The standardized meals contained approximately 400 calories (kcal) and approximately 13 g
fat. On in-clinic confinement days when study drug was not being administered, breakfast
meals contained 400 to 600 kcal. Afternoon and evening meals in the study facility were also
standardized. Components of meals (e.g., margarine, jelly, bread) were given to subjects in
individual portions (e.g., 1 tablespoon) per the approved meal schedule. The provision of
meal components in bulk (e.g., a jar of jelly for subjects to share) was not practiced. All
meals provided were approved by the sponsor. These meals were taken at approximately the
same time each day (e.g., 07:30, 12:00, and 18:00).
Assessment of bioequivalence under fed conditions was considered to be scientifically and
clinically appropriate in view of the following:
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x
Emtricitabine is recommended to be taken with or without food in accordance with the
Emtriva Summary of Product Characteristics (SmPC)
x
Tenofovir DF is recommended to be taken with food in accordance with the
Viread SmPC.
x
Rilpivirine has been shown to exhibit a significant food-effect {14064} with exposures
(Cmax, AUClast, and AUCinf) 40% lower when administered under fasted conditions
compared to administration with either a standard or a high-fat breakfast. Additionally,
the 25-mg dose of RPV was selected based on safety and efficacy (Phase 2b) and clinical
pharmacology (thorough QT/QTc) studies as the dose providing appropriate drug
exposures when administered with food. As such, subjects are instructed to take RPV
with a meal in the ongoing Phase 2b (C204) and Phase 3 studies (C209 and C215); this
method of administration will be recommended in the prescribing information for the
FDC tablet. This recommendation will also be included in the prescribing information for
the single agent RPV 25-mg tablets.
The assessment of pharmacokinetic equivalence of the 2 treatment administrations
(FTC/RPV/TDF fixed-dose combination tablet relative to coadministration of the individual
components) was determined by measures of the rate and extent of exposure (Cmax, AUClast
and AUCinf) for each analyte.
Pharmacokinetic assessments are available for a total of 34 subjects who enrolled and
completed the study. The mean (% coefficient of variation [CV]) primary pharmacokinetics
parameters for FTC, RPV, and TFV and statistical analyses for the analytes within the
Formulation 3 (test) compared to the individual components (reference) are summarized in
Table 1. FTC/RPV/TDF FDC Formulation 4 did not achieve bioequivalence (see
Module 2.7.1.3.5.2).
As observed for Formulation 3, the geometric mean ratios (test/reference) and the associated
90% confidence intervals were contained within the specified bounds of 80% to 125% for the
pharmacokinetic parameters of FTC, RPV, and TFV. Therefore, the FDC tablet containing
Formulation 3 (test) achieved bioequivalence as assessed by Cmax, AUClast, and AUCinf for all
analytes.
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Table 1.
Final
GS-US-264-0103: Statistical Comparisons of FTC, TFV, and RPV
Pharmacokinetic Parameters for Test (Formulation 3) Versus
Reference Treatment
FTC/RPV/TDF
Test Formulation
(N=34)a
FTC + RPV + TDF
Reference
(N=34)a
Geometric Least
Squares Mean
Ratio (%)
90%
Confidence
Interval
Cmax (ng/mL)
Mean (%CV)
1753.9 (23.6)
1652.8 (21.9)
105.47
100.46, 110.74
AUClast (ngh/mL)
Mean (%CV)
9416.5 (14.3)
9417.5 (13.9)
99.94
97.77, 102.16
AUCinf (ngh/mL)
Mean (%CV)
9636.3 (14.1)
9644.5 (13.6)
99.86
97.67, 102.09
Cmax (ng/mL)
Mean (%CV)
115.5 (29.6)
99.8 (30.5)
115.87
108.21, 124.06
AUClast (ngh/mL)
Mean (%CV)
3014.4 (34.5)
2597.2 (32.5)
115.71
109.13, 122.69
AUCinf (ngh/mL)
Mean (%CV)
3389.3 (39.4)
2923.3 (38.6)
115.64
108.71, 123.01
Cmax (ng/mL)
Mean (%CV)
324.7 (26.0)
291.1 (26.4)
111.01
104.19, 118.28
AUClast (ngh/mL)
Mean (%CV)
3108.2 (21.1)
3040.3 (21.3)
102.14
99.00, 105.38
AUCinf (ngh/mL)
Mean (%CV)
3313.6 (19.7)
3246.8 (19.7)
101.99
99.06, 105.00
Analyte
Parameter
FTC
RPV
TFV
GLS = geometric least-squares
FTC + RPV + TDF reference = a single dose of FTC 200-mg capsule, RPV 25-mg tablet, and TDF 300-mg tablet
FTC/RPV/TDF FDC test formulation 3 = a single dose of FDC tablet (FTC 200 mg/RPV 25 mg/TDF 300 mg)
a
Subjects 3648-3008 and 3648-3026 did not have pharmacokinetic (PK) data for a treatment pair of interest and were
excluded.
Source: Module 5.3.1.2, GS-US-264-0103 CSR, Tables 10.1, 10.2, 10.3, 10.5, 10.6, 10.7
2.5.2.3.
Effect of Food
The effect of food of FTC, RPV, TDF, Truvada, and the FTC/RPV/TDF FDC tablet is
described in Module 2.7.1.3.6.
2.5.2.3.1.
Emtriva
Emtriva capsules and oral solution may be taken with or without food. Emtricitabine
systemic exposure (area under the plasma drug concentration-time curve >AUC@) was
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unaffected while Cmax decreased by 29% when Emtriva capsules were administered with
food (an approximately 1000 kcal high-fat meal). Emtricitabine systemic exposure (AUC)
and Cmax were unaffected when 200 mg Emtriva oral solution was administered with either a
high-fat or low-fat meal.
2.5.2.3.2.
Rilpivirine
It is recommended that TMC278 be administered with a meal to ensure optimal absorption
and exposure. In the Phase 2b trial and the Phase 3 trials, subjects were instructed to take the
TMC278 tablet with a meal.
The effect of concomitant food intake on the oral bioavailability of TMC278, when
administered as a tablet, was investigated in 2 Phase 1 trials in healthy subjects, trial C102
using the Phase 2b tablet, and trial C137 using the Phase 3 tablet.
In both trials, the effect of concomitant food intake was evaluated by administering TMC278
within 10 minutes after a standardized breakfast compared to administration under fasted
conditions. In addition, trial C137 investigated the effect of a high-fat breakfast or just a
protein-rich nutritional drink.
The exposure to TMC278 was notably higher when administered with a meal. This effect
was comparable for the Phase 2b and the Phase 3 tablet. The exposure to TMC278
administered as the Phase 2b tablet (single 100-mg dose), was 1.7-fold (Cmax) and 1.5-fold
(AUClast) higher after the standardized breakfast when compared to fasted conditions.
Likewise, the mean exposure to TMC278 administered as the Phase 3 tablet (single 75-mg
dose) was 1.9-fold (Cmax) and 1.8-fold (AUClast) higher after the standardized breakfast when
compared to fasted conditions. It is anticipated that the food effect will be either similar or
less for the TMC278 25 mg once daily dose.
In addition, it was shown that the mean exposure to TMC278 was similar when administered
with a regular or a high-fat breakfast. However, the mean exposure to TMC278 was 50%
lower when administered after a protein-rich nutritional drink as compared to the
standardized breakfast. The mean exposure to TMC278 when administered after a proteinrich nutritional drink alone was comparable to that in the fasted state.
Increased bioavailability of poorly soluble drugs, such as TMC278, in the presence of food
may be explained by improved solubilization due to increased levels of bile constituents and
the presence of lipid digestion products within the intestinal lumen. Bile salts enhance
absorption of lipophilic compounds by micellar solubilization. In addition, gastric residence
time is prolonged in fed conditions, enabling longer dissolution and mixing of the drug.
It is not clear what may have caused the reduced absorption when TMC278 was administered
after the nutritional drink. Potential factors that could have contributed to this result include
the specific content of the nutritional drink, and the fact that a liquid meal was compared
with a solid meal, involving a difference in gastric residence time and gastric emptying rate.
Furthermore, there may be differences between the solid meal and the nutritional drink in
terms of the potential for binding of TMC278 to (protein) components of the meal and a
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possible effect on gastric pH. Finally, multicomponent nutritional drinks can interfere with
the disintegration and drug release from tablets in vitro and in vivo, e.g., by the formation of
a film around the tablet.
Based upon the food effect data, it is recommended that TMC278 be administered with a
meal to ensure optimal absorption and exposure. TMC278 should not be taken with a
protein-rich nutritional drink alone. There is no relevant difference in the exposure of
TMC278 when taken with a regular breakfast or a high-fat breakfast.
2.5.2.3.3.
Viread
Administration of Viread following a high-fat meal (approximately 700 to 1000 kcal
containing 40% to 50% fat) increases the oral bioavailability, with an increase in TFV
AUC0- of approximately 40% and an increase in Cmax of approximately 14%. However,
administration of Viread with a light meal did not have a significant effect on the
pharmacokinetics of TFV when compared to fasted administration of the drug. Food delays
the time to TFV Cmax by approximately 1 hour. Cmax and AUC of TFV are 326 r 119 ng/mL
and 3324 r 1370 ng·h/mL, respectively, following multiple doses of Viread 300 mg once
daily in the fed state, when meal content was not controlled. In the EU it is recommended
that Viread be taken with food.
2.5.2.3.4.
Truvada FDC tablet
Compared with fasted administration, dosing of a fixed-dose combination of TDF and FTC
with either a high-fat meal or a light meal increased the mean AUC and Cmax of TFV by 35%
and 15%, respectively, with no effect on FTC exposure (Study GS-US-104-172). The lack of
a food effect with FTC in this study is consistent with the results of the previous food effect
study with the single agent (Study FTC-111), which indicates that FTC may be taken with or
without food. The increased exposure to TFV when administered with food is consistent with
findings from previous food effect studies of the single agent (Studies GS-00-914,
GS-01-932 and GS-99-909). The applicant believes that TDF may be administered with or
without food and that the increase in plasma exposure due to the effect of food on TDF is not
of clinical relevance, as the active moiety, tenofovir diphosphate, acts intracellularly and
exhibits a protracted half life. However the EU prescribing information recommends that
Truvada be taken with food in order to optimize the absorption of tenofovir.
2.5.2.3.5.
FTC/RPV/TDF FDC tablet
In accordance with the posology of the components, the FTC/RPV/TDF FDC tablet is
recommended to be taken once daily, orally with a meal. The bioequivalence of the
FTC/RPV/TDF FDC tablet with the individual agents was demonstrated under fed conditions
and therefore supports the proposed posology.
To date, 2 bioequivalence studies (GS-US-264-0101 and GS-US-264-0103) have been
conducted in which all tablet formulations, both as FDC and separate agents, were examined
under fed conditions to determine if strict criteria for bioequivalence were met (see
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Section 2.5.2.2). Gilead Sciences is currently conducting a study (GS-US-264-0108) to
evaluate the relative bioavailability of the FTC/RPV/TDF FDC tablet (Formulation 3)
compared to a 200-mg capsule of FTC, a 25-mg tablet of RPV, and a 300-mg tablet of TDF
taken concurrently under fasted conditions. Together, data from this study and Study
GS-US-264-0103 are intended to allow descriptive analyses of the relative effect of food on
the pharmacokinetics of the components of the fixed-dose combination tablet. The last
subject observation in Study GS-US-264-0108 was 16 June 2010 and the clinical study report
is due to be completed in October 2010.
2.5.3.
Overview of Clinical Pharmacology
For detailed information on the clinical pharmacology data described in this section, refer to
Module 2.7.2.
2.5.3.1.
Pharmacology/Virology
A set of clinical pharmacology studies were conducted with the components of the
FTC/RPV/TDF FDC tablet. Two studies addressed the antiviral activity in vitro of FTC,
RPV, and TFV in 2- and 3-drug combinations (PC-264-2001, PC-264-2002). These studies
showed additive to synergistic activity for the 2-drug combinations and synergy for the
3-drug combination. A study addressed the patterns of HIV-1 resistance mutations that
emerged in vitro under selective pressure of FTC + RPV + TFV (PC-264-2003). This study
showed that M184V/I and K65R emerged, and no RPV-associated mutations developed
when the triple combination of drugs were used. The lack of cross-resistance to FTC and
TFV was shown for a large panel for HIV-1 containing RPV-associated resistance mutations
(PC-264-2004). Data for FTC, RPV and TDF are summarized in Module 2.7.2.
2.5.3.1.1.
Mechanism of Action
2.5.3.1.1.1.
Emtricitabine
Emtricitabine, an NRTI, is converted intracellularly through 3 phosphorylation reactions to
its active phosphorylated anabolite FTC-TP {4527}, {4535}. FTC-TP inhibits viral
polymerases by direct binding competition with the natural deoxyribonucleotide substrate
(deoxycytidine triphosphate, dCTP), and after incorporation into deoxyribonucleic acid
(DNA), by DNA chain termination {4249}. FTC-TP is a very weak inhibitor of mammalian
DNA polymerases D, E, H, and mitochondrial DNA (mtDNA) polymerase J {4241},
(Report TEZZ/93/0007).
2.5.3.1.1.2.
Rilpivirine
TMC278, a diarylpyrimidine derivative, is a potent NNRTI with in vitro activity against
wild-type HIV-1 and NNRTI-resistant mutants, with a median 50% effective concentration
(EC50) for HIV-1IIIB of 0.73 nM {15541}. Based on in vitro selection experiments, TMC278
has a higher genetic barrier to the development of HIV-1 resistance than EFV, DLV, or NVP
(Report TMC278-IV1-AVMR).
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2.5.3.1.1.3.
Final
Tenofovir DF
Tenofovir DF, an NtRTI, is converted to TFV by serum esterases. Intracellularly, TFV is
then converted through 2 phosphorylation reactions to its active phosphorylated anabolite,
tenofovir diphosphate {1574}. Tenofovir diphosphate inhibits viral polymerases by direct
binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine
triphosphate, dATP), and after incorporation into DNA, by DNA chain termination {1131}.
Tenofovir diphosphate is a very weak inhibitor of mammalian DNA polymerases D, E, į, İ,
and mitochondrial DNA polymerase J {1131}, {2516}.
2.5.3.1.1.4.
Tenofovir and FTC are analogs of 2 different nucleosides, adenosine and cytidine,
respectively, and do not share a common intracellular metabolism pathway. In experiments
where both drugs were incubated together at concentrations higher than achieved in the
plasma (10 PM each), the intracellular activation of TFV to tenofovir diphosphate was not
negatively influenced by the presence of FTC, and the activation of FTC to FTC-TP, was not
negatively affected by the presence of TFV (Report PC-164-2002). As tenofovir diphosphate
and FTC-TP are alternative substrates for different natural substrates, dATP and dCTP,
respectively, there should be no competition for incorporation by HIV-1 RT and subsequent
chain termination. Rilpivirine is a diarylpyrimidine derivative, a noncompetitive inhibitor of
the HIV-1 reverse transcriptase. Rilpivirine binds tightly to the allosteric NNRTI-binding
pocket on HIV-1 RT and so decreases the affinity of the enzyme for its substrate.
In Vitro Activity
In vitro studies have demonstrated potent antiviral activity of FTC, RPV, and TDF against
laboratory and clinical strains of HIV-1, including virus with reduced sensitivity to other
NRTIs and NNRTIs.
The EC50 of FTC against laboratory adapted strains of HIV-1 ranged from 0.0013 to 0.64 PM
depending on cell type and virus strain used in the assay (Reports 462 v2 and 10498 v2),
{4534}, {4541}, {4526}. With clinical isolates of HIV-1, EC50 values range from 0.002 to
0.028 PM (Report 462 v2), {4534}. Emtricitabine displays antiviral activity in vitro against
HIV-1 subtypes A, B, C, D, E, F, and G with EC50 values ranging from 0.002 to 0.075 PM
(Reports 10498 v2 and 11419 v2), and shows activity against HIV-2 (with an EC50 of 0.007
to 1.5 PM) {4534}, {4541}.
The median TMC278 (EC50) for HIV-1IIIB of 0.73 nM {15541}. Based on in vitro selection
experiments, TMC278 has a higher genetic barrier to the development of HIV-1 resistance
than EFV, DLV, or NVP. Although TMC278 demonstrated limited in vitro activity against
HIV-2 with EC50 values ranging from 2510 to 5220 nM, treatment of HIV-2 infection with
TMC278 is not recommended in the absence of clinical data.
The EC50 of TFV against wild-type HIV-1IIIB is 1 to 6 PM in T lymphoblastoid cell lines and
0.2 to 0.6 PM in peripheral blood mononuclear cells (PBMCs) {1574}, {39}. With clinical
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isolates of HIV-1, EC50 values range from 0.04 to 8.5 PM {625}. The mean EC50 values of
TFV against HIV-1 subtypes A, C, D, E, F, G, and O in PBMCs were within 2-fold of
subtype B (0.55 to 2.2 PM) {5044}. Tenofovir has an EC50 of 0.04 PM against HIV-1BaL in
primary monocyte/macrophage cells and also is active against HIV-2 in vitro, with an EC50
of 1.6 to 5.5 PM ({39}, {625}, Reports PC-104-2003 and PC-104-2013).
The anti-HIV-1 activity of the 2-drug combinations of FTC, RPV, and TFV were found to be
additive to synergistic in multiple in vitro assay systems, supporting the use of these agents in
combination in HIV-1 infected patients (Report PC-164-2001, Report PC-164-2002, Report
TMC278-IV1-AVMR, and Module 2.6.2.5). In addition, in vitro combination studies have
shown that FTC, RPV, and TFV have additive to synergistic anti-HIV-1 activity with other
approved NRTIs, NNRTIs, and PIs, as well as the integrase inhibitor elvitegravir (FTC and
TFV) {1469}, (Report PC-183-2004, Report PC-264-2001, Report 470, Report 10804, and
Report C1278-00005; see Modules 2.6.2.5 and 2.7.2.3.1.9.1).
The anti-HIV activity of the triple combination of FTC, RPV, and TFV in vitro demonstrates
synergy for anti-HIV activity and no evidence of cytotoxicity (Report PC-264-2002).
In addition to anti-HIV activity, both FTC and TFV demonstrate potent and selective
inhibition of hepatitis B virus (HBV) replication in vitro and in vivo. Tenofovir activity has
been demonstrated against both wild-type and 3TC-resistant HBV {2368}, {3467}, {9266}.
Clinical efficacy and safety experience in HIV-1 infected subjects coinfected with HBV is
described in Sections 2.5.4.8 and 2.5.5.12.5, respectively. No activity of RPV was observed
against HBV at concentrations up to 10 PM.
The principal findings of in vitro and in vivo studies that describe the resistance profiles of
FTC, RPV, and TDF are summarized in the context of virologic response to treatment in
Section 2.5.4.6 and Report PC-264-2005.
A variety of in vitro studies have been conducted to evaluate the ability of either FTC or
TFV, alone or in combination, to exert mitochondrial toxicity. Results from these studies
suggest that TFV and FTC have limited capability to inhibit human DNA polymerases or to
mediate cytotoxicity or mitochondrial damage. Rilpivirine had no effects on DNA synthesis
by human DNA polymerases. Based on these data and the clinical experience with FTC,
RPV, and TDF, the potential for mitochondrial toxicity is considered to be low.
2.5.3.2.
Clinical Pharmacodynamics
The antiviral effects of FTC, RPV, and TDF, and the relationship with dose were assessed in
clinical Phase 1 studies that supported the dose selection for investigations in the respective
Phase 2/3 clinical programs. The significant clinical efficacy demonstrated in pivotal Phase 3
studies with FTC 200 mg, RPV 25 mg, and TDF 300 mg, each administered once daily
supports the antiviral efficacy of the FTC/RPV/TDF FDC tablet. The relevant clinical data
for FTC, RPV, and TDF are detailed in Module 2.7.2.
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2.5.3.3.
Clinical Pharmacokinetics
2.5.3.3.1.
Pharmacokinetic Profiles
2.5.3.3.1.1.
Emtricitabine and Tenofovir DF
Final
Emtricitabine (see Module 2.7.2.3.1.1) and TDF (see Module 2.7.2.3.1.3) demonstrate
similar pharmacokinetic profiles that are consistent across healthy volunteers and HIV-1
infected subjects (FTC Studies FTC-101, FTC-102, FTC-106, and FTC-303 [PK substudy];
TDF Studies GS-97-901, GS-99-907 [PK substudy], and GS-00-914). Following oral
administration of FTC and TDF, both drugs are rapidly absorbed with maximum FTC and
TFV concentrations observed within approximately 1 to 2 hours of dosing with or without
food. After Cmax is achieved, plasma concentrations decline in a biexponential manner in both
cases. The median plasma half-life of FTC following a single oral dose is approximately
10 hours, which is relatively long compared with other nucleoside analogs. The median
terminal elimination half-life of TFV is approximately 17 hours, and steady-state is achieved
in approximately 3 to 4 days. In vitro binding of FTC to human plasma proteins was 4%
and independent of concentration over the range of 0.02 to 200 Pg/mL
(Report TBZZ/93/0025). Tenofovir shows low protein binding in either human plasma
(0.7%) or serum (7.2%) (Report P0504-00039).
Both FTC and TFV are eliminated primarily by renal excretion through a combination of
glomerular filtration and active tubular secretion. Approximately 70% of an oral dose of FTC
is recovered in urine as unchanged drug in subjects with normal renal function
(Study FTC-106). After intravenous administration of TFV in subjects with normal renal
function, approximately 70% to 80% of the dose is recovered in urine as unchanged TFV
within 72 hours of dosing (Study GS-96-701). Despite the common route of elimination, the
lack of effect on the pharmacokinetics of either drug when FTC and TDF are coadministered
is supported by Study FTC-114. Metabolism is a minor elimination pathway for FTC. In a
mass balance study with 14C-FTC in humans, approximately 13% of an oral dose was
recovered as metabolites, 12.9% in the urine and 0.01% in feces (Study FTC-106). A
3'-sulfoxide diastereomer of FTC accounted for 8.7% of the dose and a 2'-O-glucuronide
accounted for 4% of the dose.
2.5.3.3.1.2.
Rilpivirine
2.5.3.3.1.2.1.
Absorption of TMC278
The solubility of TMC278 drug substance is low and pH dependent. The highest solubility of
TMC278 is obtained at pH 2.0 (0.003 g/100 mL) (see Module 2.7.2.3.1.2.1). At pH values
above 2.0, drug dissolution decreases significantly (< 0.001 g/100 mL). Because an
acceptable intravenous formulation suitable for use in humans is not available, the absolute
bioavailability of TMC278 after oral administration has not been investigated.
TMC278 had intermediate permeability, and overall, TMC278 permeation is thought to
occur predominantly via a passive transcellular diffusion mechanism.
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After oral administration as a tablet formulation, TMC278 is well absorbed, with the
maximum plasma concentration attained approximately 4 hours after administration, both in
healthy subjects and in HIV-infected subjects. The rate of TMC278 absorption is not
influenced by the dose.
The impact of concomitant food intake (See Section 2.5.2.3.2) and the effect of drugs that
increase intragastric pH (see Section 2.5.3.4.2.2) on the oral bioavailability of TMC278 have
been investigated in specific clinical trials.
2.5.3.3.1.2.2.
Distribution of TMC278
After a single oral dose of 150 mg 14C-TMC278 in healthy adults (Trial C119), the blood to
plasma ratios of total 14C-radioactivity were time-independent, with values ranging between
0.65 and 0.75, indicating that TMC278 and its metabolites are predominantly distributed to
plasma and not to blood cells (see Module 2.7.2.3.1.2.2).
The in vitro plasma protein binding of TMC278, determined by equilibrium dialysis, was on
average 99.7%, irrespective of the TMC278 concentration (10 to 3000 ng/mL). TMC278 was
extensively bound to human albumin and to a lesser extent to Į1-acid glycoprotein.
The distribution of TMC278 into compartments other than plasma (e.g., cerebrospinal fluid
or genital tract secretions) has not been evaluated in humans.
2.5.3.3.1.2.3.
Metabolism and Excretion of TMC278
In Vitro and In Vivo Metabolism
The in vitro metabolism of TMC278 was studied in human hepatocytes and liver subcellular
fractions of humans and various animal species (see Module 2.7.2.3.1.2.3).
A major metabolic pathway of TMC278, representing the main in vitro biotransformation,
was aromatic hydroxylation at the pyrimidinyl moiety, followed by glucuronidation. Another
major metabolic pathway was aliphatic hydroxylation at one of the methyl groups of the
cyanoethenyl-2,6-dimethylphenyl moiety (hydroxymethyl TMC278), followed by
dehydration to form a tricyclic metabolite. Aliphatic hydroxylation in combination with
glucuronidation was also observed.
The metabolism of 14C-TMC278 in human liver microsomes revealed that the primary
TMC278 metabolism was mainly catalyzed by cytochrome P450 (CYP) 3A enzymes.
Clinical Trials
A mass-balance trial in healthy adults (Trial C119; Modules 2.7.2.3.1.2.3 and 2.7.2.2.2.2.1)
showed that most of the administered 14C-TMC278-related radioactivity from a single
150-mg dose administered as an oral solution was excreted in feces. At 168 hours after
dosing, a mean of 85.1% of the administered radioactivity was recovered in feces.
Unchanged TMC278 accounted for a mean of 25.5% of the dose in feces. The excretion of
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radioactivity in urine was limited (mean 6.1% of the administered radioactive dose). Only
trace amounts (d 0.03%) of unchanged TMC278 were detected in urine.
The metabolites of 14C-TMC278 in vivo were determined in feces, urine, and plasma
collected from healthy adults after a single oral dose of 150 mg 14C-TMC278. TMC278 was
extensively metabolized, with more than 15 metabolites detected. The most abundant
metabolite originated from aromatic hydroxylation at the pyrimidinyl moiety, accounting for
16.1% of the TMC278-related radioactivity in feces. Three other metabolites in feces each
accounted for 2.2% to 3.0% of the dose, including a carboxylic acid metabolite and
hydroxymethyl TMC278.
In plasma, unchanged TMC278 represented the major fraction of the absorbed radioactivity.
Several minor metabolites were detected in plasma, including a direct glucuronide of
TMC278 the tricyclic metabolite and hydroxymethyl TMC278.
2.5.3.3.1.2.4.
Pharmacokinetics of TMC278 after Single- and Multiple-Dose
Administration in Healthy Subjects
Data on the single-dose and multiple-dose pharmacokinetics of TMC278 in healthy subjects
are available from trials conducted with the oral solution that was used in the early Phase 1
and Phase 2a trials, with the Phase 2b tablet, and with the Phase 3 tablet (Modules 2.7.2.2.2.3
and 2.7.2.2.2.4).
After multiple-dose administration of TMC278 as the Phase 2b tablet (C103;
Module 2.7.2.2.2.4.2), the exposure to TMC278 increased dose proportionally across a dose
range of 25 to 150 mg once daily. The rate of TMC278 absorption was not influenced by the
dose; the median tmax was 4 hours. The pharmacokinetic profile of TMC278 in plasma was
generally similar after multiple-dose administration of different formulations (oral solution,
Phase 2b tablet, or Phase 3 tablet).
The comparable range of t1/2, term values across doses and the comparable range of the mean
apparent oral clearance (CL/F) after single and multiple dosing indicated that there was no
time-dependent change in clearance of TMC278 following multiple oral dosing. The
accumulation ratio of TMC278 between the first dose and steady-state was approximately
2 to 3, which concurred with the median t1/2, term of approximately 45 to 50 hours, across
trials.
2.5.3.3.1.2.5.
Pharmacokinetics of TMC278 in HIV-1 Infected Subjects
Pharmacokinetic data from intensive sampling in HIV-1 infected subjects are available from
multiple-dose administration of TMC278 using the Phase 2b tablet in the Phase 2b trial and
the Phase 3 tablet in the 2 Phase 3 trials (Module 2.7.2.2.2.6).
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In addition, population pharmacokinetic parameters are available from the Phase 2b trial, in
which subjects were treated with Phase 2b tablet dose strengths of 25, 75, or 150 mg, and
from the pooled Phase 3 trials, in which subjects were treated with the 25-mg Phase 3 tablet.
The rate of TMC278 absorption was not influenced by the dose level; the median tmax was
4 hours at all dose levels, in the different studies. Within each dose level, there was no
difference in the mean exposure to TMC278 over time. There was a less than
dose-proportional increase between the dose levels evaluated in Phase 2b, most pronounced
between the 25 and 75 mg once daily dose levels. The range of exposures observed with the
25 mg once daily dose was comparable in the Phase 2b and the Phase 3 trials.
2.5.3.3.1.2.6.
Comparison of Exposure to TMC278 Between Healthy Subjects and
HIV-1 Infected Subjects
A comparison of the exposure to TMC278 between healthy subjects and HIV-1 infected
subjects is based on across-trial comparisons of noncompartmental pharmacokinetic analyses
of TMC278 plasma concentrations (intensive sampling), and from the population
pharmacokinetic models for the Phase 2b and Phase 3 trials (Module 2.7.2.3.1.2.6).
After multiple-dose administration of TMC278 as the Phase 2b tablet at a dose of 25 mg once
daily, the mean steady-state exposure (AUC24h) to TMC278 in HIV-1 infected subjects
(Phase 2b trial C204, pharmacokinetic substudy) was in between that observed in healthy
subjects in trial C103 and trial C151. At a dose of 150 mg once daily, the mean exposure to
TMC278 was 22% to 50% lower in HIV-1 infected subjects in the pharmacokinetic substudy
of trial C204 than in healthy subjects treated with the same dose of TMC278. In the
population pharmacokinetic modeling of the Phase 2b trial, the exposure was estimated to be
20 to 30% lower in HIV-1 infected subjects compared to healthy subjects.
After multiple-dose administration of TMC278 as the Phase 3 tablet at a dose of 25 mg once
daily, the mean exposure (AUC24h and Cmax) to TMC278 was more than 30% lower in HIV-1
infected subjects in the Phase 3 pharmacokinetic substudies compared to healthy subjects in
trial C152. However, in another trial in healthy subjects (C130), the mean exposure to
TMC278 with the Phase 3 tablet at a dose of 25 mg once daily was comparable with that in
HIV-1 infected subjects in the Phase 3 pharmacokinetic substudies (Table 2). The median
tmax of TMC278 at steady-state was comparable in healthy subjects and in HIV-1 infected
subjects (5 hours and 4 hours, respectively).
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Table 2.
Final
Steady-State Pharmacokinetics of TMC278 After Administration
of TMC278 25 mg Once Daily in Healthy Subjects (Trial C130 and
C152) and in HIV-1 Infected Subjects (Trials C209 and C215,
Pharmacokinetic Substudies)
Mean r SD; tmax: Median (Range)
Healthy
Parameter
HIV-1 Infected
C130
C152
C209
C215
Day 11 (Healthy) or any time point between Week 4 and 8 (HIV-1 Infected)
N
16
57
12
32
tmax, h
5.0 (5.0 - 12.0)
5.0 (4.0 - 24.0)
4.01 (2.00 - 12.00)
4.00 (1.00 - 12.00)
Cmin, ng/mL
66.48 r 16.29
95.23 r 29.07
61.79 r 28.69
50.58 r 27.94
Cmax, ng/mL
145.5 r 31.97
246.8 r 74.36
138.6 r 66.73
132.5 r 74.79
AUC24h, ng.h/mL
2235 r 460.4
3324 r 884.0
2133 r 1016
1958 r 964.5
SD, standard deviation
N = maximum number of subjects with data.
Source: Module 2.7.2.3.1.2.6, Table 105
A lower exposure in HIV-1 infected subjects compared to healthy subjects was also observed
in the population pharmacokinetic modeling of the Phase 3 trials. This was estimated to be
approximately 40% lower in HIV-1 infected subjects in the Phase 3 trials. However, the
magnitude of this difference in exposure between HIV-1 infected subjects and healthy
subjects has to be interpreted with caution, as this was based on the comparison with a single
trial in healthy subjects (C152). As discussed above, data from other recent trials in healthy
subjects with the TMC278 Phase 3 tablet at a 25 mg once daily dose indicate that the
exposures observed in trial C152 are at the high end of the exposure range observed in
healthy subjects.
2.5.3.3.1.3.
Single-dose administration of the FTC/RPV/TDF FDC tablet resulted in plasma
concentration-time profiles of FTC, RPV, and TFV similar to those observed after the
concurrent administration of the 3 separate formulations and consistent with their established
pharmacokinetic profiles (Study GS-US-264-0103; see Section 2.5.2.2).
2.5.3.3.2.
Demographic Effects
Pooled data from 108 healthy volunteers and 20 HIV-1 infected subjects were used to assess
the influence of demographic variables on the pharmacokinetic profile of FTC (Studies
FTC-101, FTC-103, FTC-104, FTC-106, FTC-107, FTC-108, FTC-109, FTC-110, FTC-111,
and FTC-303).
In HIV-1 infected subjects, intrinsic factors that have been considered for their potential
effect on the pharmacokinetics of TMC278 include age, gender, race, body weight, estimated
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glomerular filtration rate (eGFR), and hepatitis B and/or C virus coinfection status. The
impact of these factors was evaluated in the subgroup analyses obtained in the individual and
pooled Phase 3 trials (primary 48-week analysis) in HIV-1 infected subjects. In addition, the
effect of these factors has also been explored using covariate analysis in the population
pharmacokinetic analysis of TMC278 for the pooled data from the Phase 3 trials. Where
investigated, information is also provided on the effect of intrinsic factors on the
pharmacokinetics of TMC278 administered at doses of 25, 75, or 150 mg once daily to
HIV-1 infected subjects in the Phase 2b trial.
For TDF, the relationship between demographic variables and the pharmacokinetics of TFV
were evaluated based on a pooled dataset from HIV-1 infected subjects and healthy subjects
(Studies GS-97-901, GS-99-907, and GS-00-914).
Clinically relevant differences in the pharmacokinetics of the FTC/RPV/TDF FDC tablet
with respect to demographic variables are not anticipated based on data available for the
individual agents. Pharmacokinetics by demographic variables are described in
Module 2.7.2.3.1.5. The main findings of these analyses are described below.
2.5.3.3.2.1.
Gender
x
The pharmacokinetics of FTC and TDF are similar in male and female subjects.
x
In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, a statistically
significant effect of gender on the exposure to TMC278 was observed, with a somewhat
higher exposure in females. This observed difference can be explained, at least in part, by
the lower average body weight in females compared to males, as indicated by the absence
of a significant effect of gender on the body weight-adjusted apparent oral clearance.
Similar observations were made for HIV-1 infected subjects in the Phase 2b trial, at the
different TMC278 dose levels. Also in the covariate analysis of the pooled Phase 3
pharmacokinetic data, a statistically significant effect of gender on the apparent oral
clearance of TMC278 was observed, resulting in a slightly lower (13.6%) apparent oral
clearance in females compared to males. However, this effect appeared to have no impact
on the overall inter-individual variability and had only a minor effect on explaining the
difference between the extremes of the covariate. This gender-related difference in
apparent oral clearance is therefore considered not to be of clinical relevance.
2.5.3.3.2.2.
Race
x
No pharmacokinetic differences due to race have been identified following the
administration of FTC.
x
In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, a statistically
significant effect of race on the exposure to TMC278 was observed, with a higher
exposure in Asian subjects compared to the rest of the population. This observed
difference was likely explained, at least in part, by the lower average body weight in
Asian subjects, as indicated by the absence of a significant effect of race on the body
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weight-adjusted apparent oral clearance. A similar observation was made in the Phase 2b
trial, where Asian subjects also had a somewhat higher exposure to TMC278. This
difference was less pronounced but still significant for the body weight-adjusted apparent
oral clearance, suggesting that race-related characteristics other than body weight
influenced the pharmacokinetics of TMC278 by race across the different doses in the
Phase 2b trial C204. Also in the covariate analysis of the pooled Phase 3 pharmacokinetic
data, a statistically significant effect of race on the apparent oral clearance of TMC278
was observed, resulting in a slightly lower (17.2%) apparent oral clearance in Asian
subjects compared to the rest of the population. The covariate effect of race appeared to
have no impact on the overall inter individual variability and had only a minor effect on
explaining the difference between the extremes of the covariate. This covariate induced
difference in apparent oral clearance is therefore considered not to be of clinical
relevance.
x
The numbers of subjects from racial and ethnic groups other than Caucasian were
insufficient to adequately determine potential pharmacokinetic differences among these
populations after administration of TDF.
2.5.3.3.2.3.
x
Region
In the pooled analysis of the Phase 3 trials, a statistically significant effect of region
(region 1: United States, Canada, Europe, and Australia; region 2: Africa; region 3: Asia;
and region 4: Latin America) on the exposure to TMC278 was observed in a univariate
analysis. The TMC278 exposure was somewhat higher (approximately 10% to 16%) in
HIV-1 infected subjects in Asia compared to other regions. However, in a multivariable
analysis including also trial, gender, and race as factors in addition to region, region was
no longer statistically significantly related to TMC278 exposure, while there was still a
statistically significant effect of race. This indicates that, as to be expected, the factors
race and region were likely related. A similar observation was made in the Phase 2b trial.
2.5.3.3.2.4.
Age
x
The pharmacokinetics of FTC or TFV have not been evaluated in subjects ! 65 years old.
x
Age did not have a statistically significant effect on the exposure to TMC278 in HIV-1
infected subjects in the Phase 3 trials C209 and C215. This was confirmed in the
covariate analysis of the pooled Phase 3 pharmacokinetic data, where age was not
retained as a significant covariate affecting the apparent oral clearance of TMC278.
x
The FTC/RPV/TDF FDC tablet should be administered with caution to elderly patients,
keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy in this subpopulation (see
Section 2.5.5.12.2).
x
The FTC/RPV/TDF FDC tablet is not recommended for use in children and adolescents
( 18 years, see Section 2.5.5.12.3), however a Paediatric Investigation Plan has been
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agreed with the EMA Paediatric Development Committee (EMEA-000774-PIP01-09, the
EMA Opinion is located in MAA Module 1.10). The pharmacokinetics, safety and
efficacy of FTC have been investigated in HIV-1 infected children. In general, the
pharmacokinetics of FTC in pediatric subjects are similar to those seen in adults. The
pharmacokinetics, safety, and efficacy of RPV have not been investigated in HIV-1
infected children. Data on the use of TDF in subjects aged 12 to < 18 years
(Study GS-US-104-0321) are currently under review by the CHMP. Only preliminary
data are available on the pharmacokinetics of TFV in pediatric subjects < 12 years of age
and its safety and effectiveness in this population has not been established.
2.5.3.3.3.
Renal Impairment
Two studies in non-HIV-1 infected subjects determined the pharmacokinetics of FTC
(Study FTC-107) and TFV (Study GS-01-919) in the presence of varying degrees of renal
impairment, including end-stage renal disease (ESRD) requiring hemodialysis (see
Modules 2.7.2.3.1.6.1 and 2.7.2.3.1.6.3).
In subjects with mild renal impairment, the pharmacokinetics of TFV and FTC are not
substantially altered to warrant dose adjustment.
The mean (%CV) FTC drug exposure increased from 12 (25%) Pg·h/mL in subjects with
normal renal function, to 20 (6%) Pg·h/mL, 25 (23%) Pg·h/mL, and 34 (6%) Pg·h/mL, in
patients with mild, moderate and severe renal impairment, respectively.
The mean (%CV) TFV drug exposure increased from 2185 (12%) ng·h/mL in patients with
normal renal function, to 3064 (30%) ng·h/mL, 6009 (42%) ng·h/mL, and
15,985 (45%) ng·h/mL, in patients with mild, moderate, and severe renal impairment,
respectively.
In patients with end-stage renal disease (ESRD) requiring hemodialysis, between dialysis
drug exposures substantially increased over 72 hours to 53 (19%) Pg·h/mL of FTC, and over
48 hours to 42,857 (29%) ng·h/mL of TFV.
In the pooled analysis of the Phase 3 trials in HIV-1 infected subjects, baseline eGFR did not
have a statistically significant effect on the exposure to TMC278. This was confirmed in the
covariate analysis of the pooled Phase 3 pharmacokinetic data, where eGFR was not retained
as a significant covariate affecting the apparent oral clearance of TMC278. In view of the
negligible renal excretion of TMC278 (< 1%), dose adjustment with RPV is unlikely to be
needed (Module 2.7.2.3.1.6.2).
Limited pharmacokinetic data for HIV-1 infected subjects receiving FTC/TDF with renal
impairment (Study GS-US-104-0235) suggest that the prolonged dose interval is not optimal
and could result in increased toxicity and possibly inadequate response. Furthermore, a
subgroup of patients with creatinine clearance (CLcr) between 50 and 60 mL/min who
received TDF in combination with FTC every 24 hours had a 2-4-fold higher exposure to
TFV and worsening of renal function. Therefore, a careful benefit-risk assessment is needed
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when FTC/TDF is used in patients with CLcr < 60 mL/min, and renal function should be
closely monitored. In addition, the clinical response to treatment should be closely monitored
in patients receiving FTC/TDF at a prolonged dosing interval.
Limited data from clinical studies support once daily dosing of FTC/TDF in patients with
mild renal impairment. In patients with moderate renal impairment (CLcr 30-49 mL/min)
administration of FTC/TDF every 48 hours is recommended, based on modelling of
single-dose pharmacokinetic data for FTC and TDF in non-HIV infected subjects with
varying degrees of renal impairment. In patients with severe renal impairment
(CLcr < 30 mL/min) and hemodialysis patients FTC/TDF is not recommended for patients
with severe renal impairment (CLcr < 30 mL/min) and in patients who require hemodialysis
because appropriate dose reductions cannot be achieved with the combination tablet (see
Module 2.7.2.3.1.6.4).
In view of the experience above, patients with moderate to severe renal impairment
(CLcr < 50 mL/min) require dosing interval adjustment that cannot be achieved with the
FTC/RPV/TDF FDC tablet, and therefore use of the FDC tablet cannot be recommended (see
Module 2.7.2.3.1.6.5).
2.5.3.3.4.
Hepatic Impairment
Emtricitabine is not significantly metabolized by liver enzymes; therefore, the impact of liver
impairment on the pharmacokinetics of FTC should be limited for this agent. The
pharmacokinetics of FTC have not been studied in hepatically-impaired subjects. Metabolism
is a minor pathway for the elimination of FTC ( 13% of oral dose, Study FTC-106).
Therefore, in patients with various degrees of hepatic dysfunction, little change in FTC
clearance is expected (see Module 2.7.2.3.1.7.1).
A specific trial (C130) was conducted to investigate the effects of mild and moderate hepatic
impairment on the pharmacokinetics of TMC278 administered at a dose of 25 mg once daily
in non-HIV-1 infected subjects. The steady-state exposure to TMC278 at a dose of 25 mg
once daily was higher in subjects with mild hepatic impairment compared to matched healthy
control subjects; the mean Cmax and AUC24h were 1.27- and 1.47-fold higher, respectively.
The increase in TMC278 exposure is not expected to be of clinical relevance or cause safety
concerns. In subjects with moderate hepatic impairment, the exposure to TMC278 after a
single dose was lower compared to healthy subjects (Cmax: 30% lower; AUC24h: 24% lower).
Based on the shape of the plasma concentration profiles, this appeared to be due to a
difference in the absorption of TMC278. However, at steady-state, due to the longer t1/2, term
in subjects with moderate hepatic impairment compared to matched healthy control subjects,
the exposure to TMC278 was comparable in subjects with moderate hepatic impairment and
healthy subjects. These data suggest that no dose adjustment of TMC278 is needed in
subjects with mild or moderate hepatic impairment. The effect of severe hepatic impairment
on the exposure to TMC278 has not been studied (Module 2.7.2.3.1.7.2).
The pharmacokinetics of TFV after a 300-mg dose of TDF were studied in
non-HIV-1 infected subjects with varying degrees of hepatic impairment, according to
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Child-Pugh-Turcotte (CPT) classification (Study GS-01-931 A/B). Tenofovir
pharmacokinetics were not substantially altered in subjects with hepatic impairment
compared with unimpaired subjects, suggesting that no dose adjustment of TDF is required in
these subjects (see Module 2.7.2.3.1.7.3).
The pharmacokinetics of the FTC/TDF tablet or the FTC/RPV/TDF FDC tablet have not
been studied in patients with hepatic impairment. However, based on minimal hepatic
metabolism for FTC and the renal route of elimination for TFV and FTC, no dose adjustment
would be required in patients with hepatic impairment (see Modules 2.7.2.3.1.7.4 and
2.7.2.3.1.7.5).
2.5.3.4.
Potential for Drug Interactions
Based on the clinical pharmacology of the individual agents in the FTC/RPV/TDF FDC
tablet, a targeted set of in vitro and clinical pharmacokinetic drug-drug interaction studies
were conducted to evaluate the potential for interaction of each agent with other drugs. The
potential for any drug interactions between the FTC/RPV/TDF FDC tablet and other
medications frequently used by the HIV-infected population can be assessed from available
drug interaction data and experience from clinical studies with use of concomitant
medications during treatment with FTC, RPV, and TDF (see Module 2.7.2.3.1.9). The
following sections provide an overview of the key drug interaction data and describe any
recommendations for use of the FTC/RPV/TDF FDC tablet.
2.5.3.4.1.
Both FTC and TDF are considered to have a low potential for cytochrome P450-mediated
interactions based on the results of in vitro experiments and the known renal elimination
pathways of both agents (see Module 2.7.2.3.1.9.1 and Reports V990172-104, PDM-006, and
PDM-007). Since both agents are primarily renally excreted, there is potential for interaction
with other drugs that are similarly eliminated. Drugs that decrease renal function may also
increase serum concentrations of these agents. Use of the FTC/RPV/TDF FDC tablet must be
avoided with current or recent use of nephrotoxic agents.
Results of in vitro transport studies indicate that the active tubular secretion of TFV is
mediated by human organic anion transporter (hOAT) type 1 (hOAT1) and multidrug
resistance protein type 4 (MRP4) acting in series as the major uptake and efflux transporters
in proximal tubules, respectively (Report PC-103-2001), {2520}, {7299}, {8418}, {9318},
{9863}, {10260}. The human organic anion transporter hOAT3 may play a secondary role in
the tubular uptake of TFV {7299}. Neither multidrug resistance P-glycoprotein (P-gp)
(Report AD-104-2002) nor multidrug resistance protein type 2 (MRP2,
Report AD-104-2001) appear to be involved in the tubular efflux of TFV {9318}. As the
primary transporter handling the tubular uptake of TFV, hOAT1 has been assessed for its
potential role in drug interactions between TFV and other renally secreted therapeutics
including antibiotics, anti-inflammatory agents, and other antivirals (including PIs). Under
physiologically relevant conditions, none of the tested drugs affected hOAT1-mediated
transport of TFV, indicating a low potential for renal interactions with TFV due to inhibition
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of this pathway (Reports PC-104-2010 and PC-104-2011). Similarly, PIsatazanavir,
lopinavir, and ritonavirdid not exhibit any effect on the active cellular elimination of TFV
mediated by MRP4 efflux pump {8418}, {9863}, {9864}. The results of in vitro drug
interaction studies indicate that PIs are unlikely to exert any substantial effect on the
accumulation of TFV in renal proximal tubules with consequential changes in the renal
safety profile of TDF.
After the lack of interaction between P-gp and TFV was established, efforts continued to
assess the potential transport of TDF by P-gp. Studies in human intestinal S9 fractions, the
human colon carcinoma cell line Caco-2, and Madin-Darby canine kidney (MDCKII) cells
stably transfected with the human gene that encodes P-gp, have suggested that the relative
ability of PIs to inhibit esterase activity and inhibit or induce intestinal P-gp may account for
the modest changes in plasma TFV levels when TDF is coadministered with some protease
inhibitors (Report AD-104-2010) {11255}.
The findings of in vitro pharmacodynamic investigations suggest a low potential for
intracellular drug antagonism between FTC or TFV and other antiretroviral compounds. The
anti-HIV-1 activity of the 2-drug combinations of FTC, RPV, and TFV were found to be
additive to synergistic in multiple in vitro assay systems, supporting the use of these agents in
combination in HIV-1 infected patients (Report PC-164-2001, Report PC-164-2002,
Report PC-264-2001; Report TMC278-IV1-AVMR, and Module 2.6.2.5). In addition, in
vitro combination studies have shown that both TFV, RPV, and FTC have additive to
synergistic anti-HIV-1 activity with other approved NRTIs, NNRTIs, and PIs, as well as the
integrase inhibitor elvitegravir (FTC and TFV) {1469}, (Report PC-183-2004,
Report PC-264-2001, Report 470, Report 10804, and Report C1278-00005; see
Modules 2.6.2.5 and 2.7.2.3.1.9.1).
The in vitro anti-HIV activity of the triple combination of FTC, RPV, and TFV demonstrates
moderate synergy for anti-HIV activity and no evidence of cytotoxicity
(Report PC-264-2002).
2.5.3.4.2.
Rilpivirine
Against the background of the in vitro findings and theoretical considerations for potential
drug-drug interactions, 17 clinical trials have been conducted to evaluate the effects of
coadministering TMC278 with other drugs (refer to Module 2.7.2 for more details on
individual trials). TMC278 was coadministered with various classes of drugs, including other
CYP3A substrates, CYP3A inducers or CYP3A inhibitors, a CYP2E1 substrate, and drugs
that alter intragastric pH. The evaluated drugs are either other ARV drugs, non-ARV drugs
that are frequently taken by HIV-1 infected subjects, or typical probe substrates.
2.5.3.4.2.1.
Potential for TMC278 to Affect Other Drugs
Overall, TMC278 at the dose of 25 mg once daily is not likely to have a clinically relevant
effect on the exposure of coadministered drugs.
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Most of the clinical drug-drug interaction trials were performed with a TMC278 dose of
150 mg once daily, which was the highest dose studied in the Phase 2b dose-finding trial, to
assess the maximal effect of TMC278 on other drugs within the dose range studied. With the
TMC278 dose of 25 mg once daily, any observed effect on the pharmacokinetics of other
drugs would either be similar or, more likely, lower than that observed with the TMC278
dose of 150 mg once daily because of the lower exposure to TMC278 (for more details, refer
to Module 2.7.2.3.1.9.2).
CYP3A
In vitro, TMC278 was shown to be a moderate inducer of CYP3A4 and an inhibitor of
CYP3A4 activity.
However, in vivo, there were no indications for inhibition of CYP3A activity by TMC278 at
any of the doses tested, and indications of induction of CYP3A activity by TMC278 were
apparent at the higher doses only (150 mg once daily and 300 mg once daily). With TMC278
150 mg once daily, modest induction of CYP3A activity was observed in a drug-drug
interaction trial with atorvastatin, given an increase (1.3-fold) in the AUC24h ratio of
2-hydroxy-atorvastatin to atorvastatin by coadministration with TMC278. The
CYP3A4-mediated metabolism of omeprazole on the other hand was not significantly
affected by coadministration with TMC278 150 mg once daily in vivo, as shown by the
absence of an effect on the AUC24h ratio of omeprazole sulfone to omeprazole. In a
drug-drug interaction trial with oral contraceptives, the exposure to norethindrone was
reduced by 41% in the presence of TMC278 at the dose of 150 mg once daily However, in a
second drug-drug interaction trial with oral contraceptives, TMC278 at a dose of 25 mg once
daily was shown not to affect the norethindrone exposure. In a drug-drug interaction trial
with sildenafil, using a 75 mg once daily dose of TMC278, there was no effect on the
exposure and metabolism of sildenafil, suggesting that there is also no effect of TMC278 on
CYP3A4 activity at this TMC278 dose level. This is also further supported by the doserelated effect on the change in 6-ȕ-OH-cortisol/cortisol ratio in urine, a surrogate marker for
CYP3A activity, when TMC278 was administered at doses of 75 and 300 mg once daily
(trial C131). TMC278 at the proposed dose of 25 mg once daily does not inhibit or induce
CYP3A.
P-glycoprotein
TMC278, although not a substrate for P-gp, inhibits the P-gp mediated transport of paclitaxel
with an apparent 50% inhibitory concentration (IC50) of 9.2 PM (3.4 Pg/mL) in Caco-2 cells.
An in vivo effect of TMC278 at the intestinal absorption level is unlikely, given the
therapeutic dose of TMC278 (25 mg once daily) and the fact that the in vivo TMC278 total
plasma concentrations at this dose are more than 10-fold lower compared to the high IC50
value.
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CYP2C19
In vitro studies with TMC278 indicated that TMC278 is a potent CYP2C19 inhibitor
(IC50 <5 PM [1.8 Pg/mL]) and a moderate inducer of CYP2C19.
In vivo, after repeated administration of TMC278 150 mg once daily, the AUC24h ratio of
5-hydroxyomeprazole to omeprazole increased by 27%, suggesting a modest induction of
CYP2C19-mediated metabolism by TMC278 at this high dose. This effect is probably even
less relevant or absent at the 25 mg once daily dose of TMC278, and is therefore unlikely to
result in clinically relevant interactions.
CYP2E1
In vivo, in a drug-drug interaction trial with the CYP2E1 probe substrate chlorzoxazone,
TMC278 at a dose of 150 mg once daily was shown not to inhibit or induce CYP2E1
activity.
CYP2C8 and CYP2C9
In vitro, TMC278 inhibits CYP2C8 and CYP2C9 with an inhibition constant (Ki) of 10.0 PM
(3.7 Pg/mL) and 1.7 PM (0.6 Pg/mL), respectively. Given the mean Cmax of approximately
0.13 Pg/mL in the pharmacokinetic substudy of the Phase 3 trials, the I/Ki value would be
<0.1 for CYP2C8 and CYP2C9, and therefore inhibition of CYP2C8 or CYP2C9 by
TMC278 25 mg once daily in vivo is unlikely. In vivo, there was also no relevant effect on
the pharmacokinetics of the CYP2C9 and CYP3A4 substrate ethinylestradiol by TMC278 at
doses of 150 mg once daily and 25 mg once daily.
Furthermore, the in vitro IC50 for CYP2C8/9/10 (3.99 PM [1.5 Pg/mL]) inhibition by
TMC278 was much higher than that for CYP2C19 (<0.06 PM [0.02 Pg/mL]), while in vivo,
inhibition of CYP2C19 was not observed, even at the higher dose of 150 mg once daily.
Alcohol Dehydrogenase
An in vitro investigation of the effect of TMC278 on ABC metabolism (by alcohol
dehydrogenase) in human liver cytosol indicated no inhibition potential by TMC278.
2.5.3.4.2.2.
Potential for Other Drugs to Affect TMC278
In general, the exposure to TMC278 can be affected by modulators of CYP3A enzyme
activity and by drugs that increase the gastric pH.
The primary metabolism of TMC278 is mainly catalyzed by CYP3A enzymes. Therefore,
coadministration of TMC278 and drugs that induce CYP3A could decrease TMC278 plasma
concentrations, which could potentially reduce the therapeutic effect of TMC278. This
decrease in exposure was indeed shown in vivo by the results of drug-drug interaction trials
with rifampin and rifabutin, which both significantly decreased the exposure to TMC278.
Based on this, TMC278 should not be used in combination with inducers of CYP3A
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(e.g., rifampin, rifabutin, rifapentine, St John’s wort, systemic dexamethasone,
carbamazepine, oxcarbazepine, phenobarbital, phenytoin).
Conversely, coadministration of TMC278 and drugs that inhibit CYP3A may increase
TMC278 plasma concentrations, as evidenced in vivo by the results of drug-drug interaction
trials with ketoconazole and ritonavir (rtv)-boosted PIs. The increase in TMC278 exposure
(based on Cmax) compared to the exposure obtained with TMC278 25 mg once daily that can
still be assumed to have no discernible effect on the QT interval (i.e., upper limit of the
90% confidence interval (CI) of the mean QTcF prolongation < 10 ms), was determined with
simulations based on the pooled data of the thorough QT studies with TMC278 (25 to
300 mg once daily) in healthy volunteers (for more details, refer to Module 2.7.4.5.4 and
Module 2.7.2.2.2.9). With these analyses, it was determined that there is a probability of 80%
that the upper limit of the 2-sided 90% CI of the mean change in QTcF by TMC278 remains
below 10 ms at an increase in exposure (based on Cmax) of 85% (i.e., 1.85-fold) compared to
the observed Cmax at the 25 mg once daily dose in healthy volunteers. In none of the
performed drug-drug interaction trials, including several with CYP3A inhibitors
(ketoconazole, rtv-boosted darunavir, rtv-boosted lopinavir), did the Cmax of TMC278
increase by more than 85%. The observed interactions are thus not expected to be of clinical
relevance or cause safety concerns, and therefore do not result in the need for dose
adjustment.
As mentioned above, a number of the clinical drug-drug interaction trials were performed
with a TMC278 dose of 150 mg once daily. TMC278 exhibits linear pharmacokinetics up to
a dose of 150 mg once daily in healthy subjects, while in HIV-1 infected subjects, the
increase in exposure across doses of 25 to 150 mg once daily was less than
dose-proportional. This indicates that there is no saturation of the TMC278 metabolism up to
the 150 mg once daily dose, as saturation would lead to a more than dose-proportional
increase in TMC278 exposure. In the absence of metabolic pathway saturation, the effect of
metabolic inhibitors such as ketoconazole on the pharmacokinetics of TMC278 at a dose of
25 mg once daily should not exceed the effect observed with TMC278 at a dose of
150 mg once daily Therefore, the dosing implications based on the results of the
pharmacokinetic drug-drug interaction trials with TMC278 at a dose of 150 mg once daily
can be extrapolated to a dose of TMC278 25 mg once daily.
The proposed prescribing information does not include the TMC278 dose used in the drugdrug interaction trials in the pharmacokinetic interaction table summarizing the outcome of
these trials, unless required otherwise by health authorities. As a number of these trials are
performed with a higher dose compared to the recommended dose of TMC278, the intent is
to avoid any potential confusion towards dosing requirements for TMC278 in combination
with these other comedications. Misinterpretation of the information provided in the
prescribing information could lead to overdosing of TMC278.
The solubility of TMC278 is pH dependent (see Section 2.5.3.3.1.2.1). Drugs that alter
intra-gastric pH may affect the solubility of TMC278 (i.e., reduced solubility at higher pH) in
vivo and can therefore also indirectly affect the absorption of TMC278. This was shown in
vivo in drug-drug interaction trials with omeprazole and famotidine, which both significantly
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decreased the exposure to TMC278 150 mg once daily when coadministered. Based on this,
TMC278 should not be used in combination with proton pump inhibitors (e.g., omeprazole,
lansoprazole, rabeprazole, pantoprazole, esomeprazole) as coadministration may cause
significant decreases in TMC278 plasma concentrations. This may result in loss of
therapeutic effect of TMC278. For drugs with a short-lived effect on intragastric pH, such as
the histamine-2 (H2)-antagonists and antacids, an effect on TMC278 exposure can be avoided
by separating the intake of the drugs in time, as has been shown in the drug-drug interaction
trial with famotidine. The combination of TMC278 and H2-receptor antagonists or antacids
should be used with caution as coadministration may cause significant decreases in TMC278
plasma concentrations. H2-receptor antagonists should only be administered either 12 hours
before or 4 hours after TMC278, and antacids should only be administered either 2 hours
before or 4 hours after TMC278.
An additional trial (C154) is ongoing to investigate the interaction between omeprazole and
TMC278 administered at doses of 25 and 50 mg once daily.
Details on trials studying the potential for drugs to affect TMC278 are presented in
Module 2.7.2.3.1.9.2.
2.5.3.4.3.
Clinically Important Drug Interactions
2.5.3.4.3.1.
Emtricitabine
No clinically relevant drug interactions have been identified between FTC and the
coadministered drugs investigated (i.e., TDF, d4T, indinavir (IDV), and zidovudine (ZDV)
and famciclovir (Studies FTC-114, FTC-103, FTC-104, and FTC-115, and FTC-108).
2.5.3.4.3.2.
Rilpivirine
When TMC278 was coadministered with didanosine (ddI) or TDF in healthy subjects, no
clinically relevant changes occurred in the pharmacokinetic parameters for TMC278 or either
coadministered drug (Trials C106 and C104). In addition, no treatment effect was shown for
the urinary excretion of TFV in the presence of TMC278. TDF and ddI can be
coadministered with TMC278 without dose adjustment for either drug. However, intakes of
TMC278 and ddI need to be separated in time due to differences in meal requirements (ddI is
recommended for administration on an empty stomach and TMC278 with a meal).
The effects of TMC278 on other NRTIs, and vice versa, have not been formally evaluated.
Because TMC278 has negligible renal elimination (< 1%), no clinically relevant drug-drug
interactions are expected between drugs that are primarily renally eliminated and TMC278.
These drugs include NRTIs such as ABC, FTC, 3TC, d4T, and AZT. In the Phase 2b trial
C204 the TMC278 dose level did not affect the pharmacokinetics of AZT and
AZT-glucuronide. Also, the pharmacokinetics of TMC278 are not expected to be affected by
these NRTIs. Therefore, TMC278 can be coadministered with NRTIs without dose
adjustments.
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Final
As mentioned above, TMC278 can be coadministered with lopinavir (LPV)/rtv (Trial C105)
or with darunavir (DRV)/rtv (Trial C112) without dose adjustments. No drug-drug
interaction trials have been performed with TMC278 and other PIs (either rtv-boosted or
unboosted).
No clinically relevant drug-drug interaction is expected when TMC278 is coadministered
with the integrase strand transfer inhibitor raltegravir or with the CCR5 antagonist maraviroc,
given the facts that these drugs do not affect pH or CYP3A enzyme activity at the
recommended dose in vivo, and TMC278 25 mg once daily is not expected to impact the
metabolism of these drugs.
In conclusion, TMC278 has a well-characterized drug-drug interaction profile and can be
used without dose modification or adjustment with all currently available N(t)RTIs, the
boosted PIs DRV/rtv and LPV/rtv, and with raltegravir and maraviroc. Drugs that alter
intra-gastric pH may affect the solubility of TMC278, therefore TMC278 should not be
coadministered with proton pump inhibitors since coadministration may cause significant
decreases in TMC278 plasma concentrations. For drugs with a short-lived effect on
intra-gastric pH, such as the H2-antagonists and antacids, an effect on TMC278 exposure can
be circumvented by separating the intake of the drugs in time. TMC278 should not be taken
with CYP3A inducers as these could decrease TMC278 plasma concentrations, and
potentially reduce the therapeutic effect of TMC278. TMC278 can be used with many other
medications generally used in HIV-1 infected patients.
A summary of coadministration recommendations based on drug-drug interaction trials or
predicted interaction for TMC278 is presented in Table 3.
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Table 3.
Final
Coadministration Recommendations Based on Drug-Drug
Interaction Trials or Predicted Interaction (Rilpivirine)
Coadministration without Dose
Adjustment
Coadministration with specific
instructions
Coadministration Not
Recommended
x
N(t)RTIs, other than ddI
(e.g., TDF, ABC, FTC, 3TC,
d4T, AZT)
x
x
x
boosted PIs LPV/rtv and
DRV/rtva
x
raltegravir, maraviroc
ddI (which should be
administered on an empty
stomach) should be administered
separated in time from TMC278
(which should be administered
with a meal).
x
ribavirin
x
x
x
azole antifungal agents
(including ketoconazole)
x
atorvastatin
proton pump inhibitors
(e.g., omeprazole,
lansoprazole, rabeprazole,
pantoprazole, esomeprazole)
x
estrogen- and/or
progesterone-based
contraceptives
when coadministering with
methadone, dose adjustment is
not needed when initiating
treatment with TMC278 but
clinical monitoring for methadone
withdrawal symptoms is
recommended. Methadone
maintenance therapy may need to
be adjusted in some patients.
inducers of CYP3A
(e.g., rifampin, rifabutin,
rifapentine, St John’s wort,
systemic dexamethasone,
carbamazepine,
oxcarbazepine,
phenobarbital, phenytoin).
x
paracetamol
a
x
H2-antagonists (e.g., famotidine)
or antacids, can be coadministered
if separated in time.
x
clarithromycin, erythromycin, and
troleandomycin may cause an
increase in the plasma
concentrations of TMC278.
Where possible, alternatives such
as azithromycin should be
considered.
The combination of TMC278 with other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir,
saquinavir/ritonavir, tipranavir/ritonavir) or unboosted PIs (atazanavir, indinavir, nelfinavir) has not been studied;
coadministration may cause an increase in the plasma concentrations of TMC278.
2.5.3.4.3.3.
Tenofovir DF
No clinically relevant pharmacokinetic interactions between TDF and other antiretroviral
drugs tested (i.e., abacavir, EFV, FTC, indinavir, 3TC, LPV/r, nelfinavir, or
saquinavir/ritonavir) have been observed, with the exception of increased ddI exposure and
decreased atazanavir (without ritonavir) described below. After multiple dosing to non-HIV
infected subjects receiving either chronic methadone maintenance therapy, oral
contraceptives, or single doses of ribavirin, steady-state TFV pharmacokinetics were similar
to those observed in previous studies, indicating a lack of clinically significant drug
interactions between these agents and TDF.
Atazanavir/Ritonavir
In subjects failing antiretroviral therapy, addition of TDF to rtv-boosted atazanavir (300 mg)
resulted in a trend towards reduction of both ritonavir and atazanavir pharmacokinetic
parameters (PUZZLE 2 study) {6043}. The AUC and Cmin of atazanavir were decreased by
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Final
approximately 25% and 23%, respectively, but were 1.2- and 4-fold higher than the
respective values observed for atazanavir 400 mg when given alone in healthy volunteers. It
is recommended that TDF should only be administered with boosted atazanavir (300 mg with
100 mg ritonavir).
Lopinavir/Ritonavir
Coadministration of TDF and LPV/r in Studies GS-00-909 and GS-01-943 resulted in an
approximate 30% increase in Cmax and AUCtau of TFV relative to administration of TDF
alone. This increase in TFV exposure is not considered clinically relevant with respect to an
alteration in the clinical safety or efficacy profile of TDF and does not require a dose
modification. Results of these 2 studies, when assessed alone or in a pooled analysis,
established that TDF does not have a clinically significant effect on the pharmacokinetics of
LPV/r and that a high lopinavir inhibitory quotient is maintained with their concomitant use.
Although Study GS-00-909 showed that systemic exposures (AUCtau) of lopinavir and
ritonavir were 15% and 24% lower when dosed with TDF versus when dosed alone, in
Study GS-01-943 TDF did not affect the steady-state pharmacokinetics of lopinavir or
ritonavir. The numerical differences observed between the 2 studies are likely due to a
variety of factors that may include, but are not limited to, subject compliance to the study
protocol, sampling variability, subject demographics, and meal types. Study M02-418 has
demonstrated the efficacy and safety of TDF in PI regimens with once or twice daily LPV/r
(see Section 2.5.4.4.3).
Coadministration with Didanosine (ddI)
In drug interaction studies of TDF and ddI (Videx), the Cmax and AUC of ddI 400 mg,
administered as either the buffered tablets or enteric-coated capsules, increased significantly
(Studies GS-00-909 and GS-01-932). The likely mechanism of this interaction is inhibition
of purine nucleoside phosphorylase (PNP) by TFV, which decreases PNP-mediated
metabolic degradation of ddI and, hence, increases ddI drug levels {6054}. However, when a
reduced dose of ddI (250-mg enteric-coated [EC] capsules) was administered in the fasted
state 2 hours before TDF, systemic exposures to ddI were similar to those seen with the
400-mg enteric-coated capsules alone (Study GS-02-984). In a study sponsored by
Bristol-Myers Squibb Company, 250 mg or 325 mg of ddI EC coadministered with 300 mg
of TDF and food resulted in ddI exposures that were similar to 400 mg of ddI (EC) fasted
{4620}.
A possible outcome of the increased AUC of ddI with concomitant administration of TDF
would be an increased incidence of ddI-related adverse events (AEs), specifically
pancreatitis, which is dose-related {6266}. Safety data from clinical studies of TDF did not
indicate a higher risk of ddI-related AEs in subjects coadministered TDF and ddI. From
individual case reports of suspected drug interactions received during postmarketing
experience, it is difficult to determine whether TDF increased the risk of ddI-related adverse
reactions. The proposed FTC/RPV/TDF prescribing information describes that rare cases of
pancreatitis and lactic acidosis, sometimes fatal, have been reported following
coadministration of ddI and TDF.
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Preliminary analyses of several small studies in antiretroviral-naive subjects treated with a
regimen of TDF, ddI (250 mg), and EFV {6923}, {7399}, {7325} indicated a higher than
expected incidence of early virological failure and emergence of resistance. Suppression of
CD4 cell counts has been observed in patients receiving TDF with ddI at a dose of 400 mg
daily.
The EU prescribing information states that coadministration of TDF and ddI is not
recommended.
2.5.3.4.3.4.
The FTC/RPV/TDF FDC tablet
Based upon experience with the components, coadministration of FTC/RPV/TDF FDC tablet
and ddI is not recommended, since the exposure of ddI is significantly increased following
coadministration with TDF. In addition, coadministration of the FTC/RPV/TDF FDC tablet
with proton pump inhibitors and inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine,
St John’s wort, systemic dexamethasone, carbamazepine, oxcarbazepine, phenobarbital,
phenytoin) is not recommended.
The FTC/RPV/TDF FDC tablet should not be coadministered with related drugs that contain
the same active components (i.e., FTC, RPV, or TDF), including Emtriva, RPV, Viread,
Truvada, and Atripla. Because of similarities with FTC or with TDF, FTC/RPV/TDF FDC
tablets should not be coadministered with other cytidine analogs, such as 3TC (including
Combivir, Epivir, Epivir-HBV, Kivexa [Epzicom], and Trizivir), or with Hepsera
(adefovir dipivoxil).
2.5.3.5.
Summary of Clinical Pharmacology
Emtricitabine and TFV are potent and selective inhibitors of HIV-1. They are phosphorylated
intracellularly through nonoverlapping pathways and in combination show no antagonism for
the formation of their active metabolites. The anti-HIV-1 activity of the 2-drug combinations
of FTC, RPV, and TFV were found to be additive to synergistic in multiple in vitro assay
systems.
The pharmacokinetic profiles of the separate formulations of FTC, RPV, and TDF, including
studies in HIV-1 infected subjects and certain special populations, have been well
established. Clinically relevant differences in the pharmacokinetics of the FTC/RPV/TDF
FDC with respect to demographic variables are not anticipated based on data available for
FTC, RPV, and TDF.
Both FTC and TFV are primarily renally excreted intact. In subjects with mild renal
impairment, the pharmacokinetics of TFV and FTC are not substantially altered to warrant
dose adjustment. Dosing interval adjustment is required in patients with CLcr between 30 and
49 mL/min (one FTC/TDF tablet every 48 hours) and FTC/TDF tablets are not recommended
for patients with CLcr < 30 mL/min and in patients who require hemodialysis. The proposed
prescribing information for the FTC/RPV/TDF tablet states that patients with moderate to
severe renal impairment (CLcr < 50 mL/min) require dosing interval adjustment that cannot
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Final
be achieved with the FTC/RPV/TDF FDC tablet, and therefore use of the FDC tablet cannot
be recommended (see Sections 2.5.5.12 and 2.5.6).
The FTC/RPV/TDF FDC tablet should not be administered concomitantly with other
medicinal products containing any of the same components (including FTC, RPV, TDF,
FTC/TDF, or EFV/FTC/TDF). Due to similarities with FTC, the FTC/RPV/TDF FDC tablet
should not be administered concomitantly with other cytidine analogues, such as lamivudine.
The FTC/RPV/TDF FDC tablet should not be administered concomitantly with adefovir
dipivoxil.
Based upon the significant increase in exposure to ddI following coadministration with TDF,
coadministration of the FTC/RPV/TDF FDC tablet with ddI is not recommended.
No clinically relevant drug interactions have been identified between FTC and the
coadministered drugs investigated. Based on the drug-drug interaction profile of RPV (see
Section 2.5.3.4.2), the FTC/RPV/TDF FDC tablet should not be coadministered with proton
pump inhibitors since coadministration may cause significant decreases in TMC278 plasma
concentrations. For drugs with a short-lived effect on intragastric pH, such as the
H2-antagonists and antacids, an effect on RPV exposure can be circumvented by separating
the intake of the drugs in time. The FTC/RPV/TDF FDC tablet should not be taken with
CYP3A inducers as these could decrease TMC278 plasma concentrations, and potentially
reduce the therapeutic effect of RPV. No clinically relevant pharmacokinetic interactions
between TDF and other antiretroviral drugs tested. After multiple dosing to non-HIV infected
subjects receiving chronic methadone maintenance therapy, oral contraceptives, or
single doses of ribavirin, steady-state TFV pharmacokinetics indicated a lack of clinically
significant drug interactions between these agents and TDF.
No drug interaction studies have been conducted with the FTC/RPV/TDF FDC tablet on the
basis that available drug interaction data and clinical study experience with use of
concomitant medications during treatment with the individual dosage forms are sufficient to
allow assessment of the potential for any drug interactions between the FDC tablet and other
medications frequently used by the HIV infected population. The proposed prescribing
information for the FTC/RPV/TDF FDC tablet describes all relevant drug interactions.
2.5.4.
Overview of Efficacy
More detailed information on the results of individual efficacy trials is provided in
Module 2.7.3. The use of FTC/RPV/TDF FDC tablets indicated for the treatment of HIV-1
infection is supported by data from the individual components (FTC, RPV, and TDF), as well
data from studies with FDCs of 2 of the components (FTC/TDF) and studies with all 3 of the
components. In this overview of efficacy, data are presented for Truvada (see
Section 2.5.4.4) and the FTC/RPV/TDF FDC tablet (see Section 2.5.4.5). See Module 2.7.3
for efficacy data for FTC, RPV, and TDF (cross references for results of individual studies
are provided below).
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2.5.4.1.
Final
Efficacy of Emtricitabine
The following supportive studies for FTC are described in Module 2.7.3.2.1:
x
FTC-301A: Module 2.7.3.2.1.1.1
x
FTC-302: Module 2.7.3.2.1.1.2
x
FTC-303: Module 2.7.3.2.1.2.1
2.5.4.2.
Efficacy of Rilpivirine
The 2 Phase 3 registrational studies, Trial C209 and Trial C215, are summarized in
Section 2.5.4.5. The following supportive studies for RPV are described in Module 2.7.3.2.2:
x
TMC278-C204: Module 2.7.3.2.2.2
x
R278474-C201: Module 2.7.3.2.2.3.1
x
R278474-C202: Module 2.7.3.2.2.3.2
2.5.4.3.
Efficacy of Tenofovir DF
The following supportive studies for TDF are described in Module 2.7.3.2.3:
x
GS-99-903: Module 2.7.3.2.3.1.1
x
GS-98-902: Module 2.7.3.2.3.2.1
x
GS-99-907: Module 2.7.3.2.3.2.2
2.5.4.4.
Efficacy of the Truvada FDC Tablet
The use of the Truvada tablet is principally supported by data from Studies GS-01-934,
GS-99-903, and M02-418, as follows:
x
GS-01-934 is a completed, Phase 3, 288-week, open-label study, in which the once-daily
regimen of FTC, TDF, and EFV (administered as the individual products
[FTC + TDF + EFV] for the first 96 weeks and subsequently as the fixed-dose
combination of FTC/TDF (Truvada) and EFV [FTC/TDF + EFV] through 144 weeks)
was compared with the fixed-dose combination of Combivir administered twice daily and
EFV once daily (CBV + EFV). After completing 144 weeks of treatment, subjects from
both treatment groups switched to a once-daily regimen of FTC, TDF, and EFV (as the
Atripla tablet) in a 96-week extension period (144 weeks at sites in EU countries where
Atripla was not launched at the time) (see Module 2.7.3.2.4.1).
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x
GS-99-903 is an ongoing, Phase 3, 624-week study in which the regimen of
TDF + 3TC + EFV was compared with a regimen of d4T + 3TC + EFV in a
double-blinded fashion for the first 144 weeks; from Week 144 to Week 480, patients at
selected sites received open label TDF + 3TC + EFV; from Weeks 480 to 624 the
regimen of TDF + 3TC + EFV changed to open label FTC/TDF (Truvada) + EFV.
Subjects who were randomized to TDF in the double-blind phase continued TDF
treatment in the open-label phase. Subjects who were randomized to d4T in the
double-blind phase were switched from d4T to TDF in the open-label phase. The
experience with the TDF + 3TC + EFV regimen is relevant to the efficacy of the Truvada
tablet because (a) 3TC is a cytidine analog that is structurally closely related to FTC;
(b) the resistance profiles of 3TC and FTC, characterized by M184V/I development, are
similar; and (c) in Study FTC-303, FTC demonstrated equivalent antiviral efficacy and
safety to 3TC when each was administered in a triple combination regimen to stable
treatment-experienced subjects (see Module 2.7.3.2.4.2).
x
M02-418 was a Phase 3, 96-week, open-label, randomized, multicenter study in which
antiretroviral-naive, HIV infected subjects received FTC and TDF once daily in
combination with a PI (800 mg/200 mg LPV/r once daily or 400 mg/100 mg LPV/r twice
daily) (see Module 2.7.3.2.4.3).
Studies GS-01-934, GS-99-903, and M02-418 were of an adequate design and duration, as
recommended in applicable regulatory guidance, to establish the efficacy and safety of the
antiretroviral regimens under investigation for the treatment of HIV-1 infection. The main
study design and population characteristics are summarized in Table 4.
Supportive evidence for the efficacy of Truvada is provided from studies in which
antiretroviral-experienced subjects switched their NRTIs to Truvada
(Studies GS-MC-164-0111, GS-US-164-0107, GS-DE-164-0106, and GS-ES-164-0154) and
an open-label single group study in antiretroviral-naive subjects (Study GS-US-164-0115).
The following supportive studies are described in Module 2.7.3.2.5:
x
GS-MC-164-0111: Module 2.7.3.2.5.1
x
GS-ES-164-0154: Module 2.7.3.2.5.2
x
GS-US-164-0107: Module 2.7.3.2.5.3.1
x
GS-DE-164-0106: Module 2.7.3.2.5.3.2
x
GS-US-164-0115: Module 2.7.3.2.5.3.3
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Table 4.
Principal Clinical Studies that Support Use of the Truvada Tablet – Design and Population
Characteristics
Study
GS-01-934
Final
Design
Randomized (1:1),
open-label, activecontrolled,
noninferiority study
Population
Treatment-naive
subjects (HIV-1
RNA ! 10,000
copies/mL)
Treatment
Regimens
No. of
Subjectsa
EFVFTCTDF to 511
Week 96, then
EFV+FTC/TDF
vs
EFVCombivir
HIV-1 Characteristics at
Study Entry (Mean)
Duration
Demographics
288 weeks
(completed)
Male (86%)
White (59%)
Mean age 38 years
HIV-1 RNA 5.01 log10
copies/mL
51% ! 100,000 copies/mL
CD4 count 245 cells/mm3
144 weeks
Male (74%)
double-blind White (64%)
phase,
Mean age 36 years
followed by
336-week
open-label
phase at
selected
centers
(ongoing)
HIV-1 RNA 4.9 log10
copies/mL
43% ! 100,000 copies/mL.
CD4 count 279 cells/mm3
From Week 144:
Atripla for all
subjects
GS-99-903
Randomized (1:1),
double-blind, activecontrolled study
CONFIDENTIAL
Treatment-naive
subjects (HIV-1
RNA ! 5000
copies/mL)
Up to Week 480
600
TDF+3TC+EFV
vs
d4T+3TC+EFV
Week 480 to Week
624 TDF+EFV vs
d4T+3TC+EFV
At selected centers
after Week 144,
TDF+3TC+EFV
for all subjects
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Study
M02-418
Design
Randomized (3:2),
open-label, activecontrolled,
noninferiority study
Population
Treatment-naive
subjects (HIV-1
RNA ! 1000
copies/mL)
Final
Treatment
Regimens
FTC+TDF+LPV/r
(800 mg/200 mg
once daily or
400 mg/100 mg
twice daily)
No. of
Subjectsa
190
Duration
Demographics
96 weeks
(completed)
Male (78%)
White (54%)
Mean age 38 years
Study Entry (Mean)
HIV-1 RNA 4.9 log10
copies/mL in the once daily
group and 4.7 log10
copies/mL in the twice
daily group
CD4 count 266 cells/PL in
the once daily group and
250 cells/PL in the twice
daily group
a
Number of subjects randomized who received at least 1 dose of study medication.
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2.5.4.4.1.
Final
Efficacy in Study GS-01-934
In Study GS-01-934, both the FTC + TDF + EFV and CBV + EFV treatment groups
demonstrated potent efficacy through 48 weeks of treatment (Table 32 has information
regarding longer term data). The percentage of responders who achieved and maintained
confirmed HIV-1 ribonucleic acid (RNA) 400 and 50 copies/mL (US FDA time-to-lossof-virologic-response [TLOVR] algorithm analysis) was significantly higher in the
FTC + TDF + EFV group compared with the CBV + EFV group for both the modified
intent-to-treat (MITT) analysis set and the intent-to-treat (ITT) analysis set (Table 5). The
MITT set excluded subjects who were antiretroviral treatment-experienced or had primary
NNRTI resistance mutations at baseline. The ITT set included all subjects who were
randomized into the study, received at least 1 dose of study medication, and had no major
protocol eligibility violations, e.g., prior antiretroviral treatment.
Table 5.
GS-01-934: Treatment Outcomes at Week 48 (TLOVR Analysis)
FTCTDFEFV
Treatment Outcome at Week 48
Responder (HIV-1 RNA 400 copies/mL), MITT
p-valuea
Difference (95% CI)
a
Difference (95% CI)
a
Difference (95% CI)
%
177/243
73%
179/254
71%
171/243
70%
173/254
68%
11% (4% to 19%)
207/255
81%
11% (3% to 18%)
194/244
80%
0.021
b
Responder (HIV-1 RNA 50 copies/mL), ITT
p-value
84%
n/N
0.005
b
Responder (HIV-1 RNA 50 copies/mL), MITT
p-value
206/244
%
0.002
b
Responder (HIV-1 RNA 400 copies/mL), ITT
p-value
n/N
CBVEFV
a
Difference (95% CI)b
9% (2% to 17%)
195/255
77%
0.034
9% (1% to 16%)
a
b
The p-value was based on the Cochran-Mantel-Haenszel test stratified on baseline CD4 cell count.
The difference and 95% confidence interval were stratum weighted on baseline CD4 cell count using normal
approximation.
Source: Module 5.3.5.1, GS-01-934 48-Week CSR, Section 11.1, Tables 11, 12, 13, and 14
Noninferiority was predefined for the 48-week primary endpoint as a 95% CI of the
treatment difference (FTC + TDF + EFV group minus CBV + EFV group) in the proportion
of subjects with sustained viral suppression below 400 copies/mL with a lower bound greater
than 0.13. Because the 95% CIs (MITT and ITT) for the treatment effect lie entirely above
the limit of t 0.13 required for demonstration of noninferiority and, furthermore, lie entirely
above zero, and because the p-values support rejection of the null hypothesis of no difference
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Final
between the treatment groups, the FTC + TDF + EFV regimen was concluded to be superior
to the CBV + EFV regimen.
The once-daily regimen of EFV + FTC + TDF demonstrated continued significant and potent
antiretroviral efficacy through 144 weeks of treatment in Study GS-01-934. A significantly
higher proportion of subjects in the FTC + TDF group (71%, 161/227) compared with the
Combivir group (58%, 133/229) were Week 144 responders (HIV-1 RNA < 400 copies/mL;
p = 0.004; 95% CI, 4% to 22%, Table 6). Similarly, the proportion of Week 144 responders
(HIV-1 RNA < 50 copies/mL) was higher for the FTC + TDF group (64%, 146/227)
compared with the Combivir group (56%, 130/231), although the difference was not
statistically significant (p = 0.082).
Table 6.
GS-01-934: Treatment Outcomes at Week 144 (TLOVR Analysis,
Week 144 Efficacy Analysis Set)
EFV + FTC + TDF
Treatment Outcome at Week 144
n/N
161/227
Responder (HIV-1 RNA 400 copies/mL)
p-valuea
Difference (95% CI)
71%
n/N
%
133/229
58%
130/231
56%
0.004
b
13% (4% to 22%)
146/227
Responder (HIV-1 RNA 50 copies/mL)
p-valuea
Difference (95% CI)
%
EFV + Combivir
64%
0.082
b
8% (1% to 17%)
a
b
The p-value was based on the Cochran-Mantel-Haenszel test stratified on baseline CD4 cell count.
The difference and 95% confidence interval were stratum weighted on baseline CD4 cell count using normal
approximation.
Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Table 14
Significantly greater proportions of subjects in the FTC + TDF group compared with the
Combivir group achieved suppression of plasma HIV-1 RNA to 400 copies/mL and
50 copies/mL at Week 144 in both the ITT missing-or-switch-equals-failure and the ITT
missing-equals-failure (M = F) analyses. The 144-week results also demonstrate high rates of
virologic response to treatment with EFV +FTC + TDF in subjects with high baseline viral
load (plasma HIV-1 RNA ! 100,000 copies/mL) and subjects with CD4 cell counts
t 200 cells/mm3.
Changes in plasma HIV-1 RNA concentrations from baseline to Week 144 were similar
between the 2 treatment groups in Study GS-01-934. Mean decreases of 3.32 log10 copies/mL
for the FTC + TDF group and 3.30 log10 copies/mL for the Combivir group were observed
(Figure 1).
CD4 cell counts increased over time for both treatment groups in Study GS-01-934
(Figure 2). At Week 144, mean increases of 312 cells/mm3 for the FTC + TDF group and
271 cells/mm3 for the Combivir group were observed.
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Figure 1.
Final
GS-01-934: Mean (95% CI) Change from Baseline in HIV-1 RNA
by Study Visit (AT Analysis Set)
Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Figure 9
Figure 2.
GS-01-934: Mean (95% CI) Change From Baseline in CD4 Cell
Count (AT Analysis Set)
Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Figure 10
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2.5.4.4.2.
Final
Efficacy in Study GS-99-903
In Study GS-99-903, the regimens of TDF + 3TC + EFV and d4T + 3TC + EFV
demonstrated potent and durable efficacy during 144 weeks of treatment. At Weeks 48, 96,
and 144, the percentages of subjects with HIV-1 RNA levels 400 copies/mL and
50 copies/mL were similar between the treatment groups (Table 7).
Table 7.
GS-99-903: Summary of Response Rates of HIV-1 RNA 400 and
50 Copies/mL (ITT Population, Missing/Switch = Failure)
Response Rate
TDF+3TC+EFV
(N=299)
d4T+3TC+EFV
(N=301)
Difference
(TDF-d4T) 95% CIa
400 copies/mL, n/N (%)
Week 48
239/299
(80%)
253/301
(84%)
4% (10%, +2%)
Week 96
226/299
(76%)
214/301
(71%)
+4% (3%, +11%)
Week 144
211/299
(71%)
193/301
(64%)
+7% (1%, +14%)
Week 48
228/299
(76%)
240/301
(80%)
3% (10%, +3%)
Week 96
217/299
(73%)
204/301
(68%)
+5% (2%, +12%)
Week 144
203/299
(68%)
188/301
(63%)
+6% (2%, +13%)
50 copies/mL, n/N (%)
a
Stratum weighted difference in percent and stratum weighted 95% confidence interval for difference in percent.
Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144 Tables 8.2 and 10.2
Following 144 weeks of double-blind treatment, there was a high proportion of subjects with
HIV-1 RNA < 400 copies/mL and < 50 copies/mL: 71% and 68%, respectively, for the
TDF + 3TC + EFV group compared with 64% and 63%, respectively, for the
d4T + 3TC + EFV group. Subgroup analyses at Week 144 confirmed high rates of virologic
response in subjects with baseline viral load ! 100,000 copies/mL and with CD4 cell count
200 cells/mm3 treated with the TDF + 3TC + EFV regimen.
Durable viral load suppression was demonstrated throughout this extended treatment period,
and was accompanied by increasing CD4 cell counts from baseline levels (Figure 3 and
Figure 4).
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Change in HIV-1 RNA
Figure 3.
Final
GS-99-903: Mean (95% CI) Change from Baseline in Plasma
HIV-1 RNA Levels (ITT Analysis Set)
0
0
-1
-1
-2
-2
-3
-3
-4
-4
-5
-5
BL
8
16
24
32
40
48
56
64
72
80
88
96
120
144
243
242
242
237
Weeks on Study
TDF+3TC+EFV: 299 289 285 280 273 264 272 261 259 258 253 255 253
d4T+3TC+EFV: 301 288 284 283 271 268 273 269 260 262 257 256 253
Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144 Figure 2.1
Change in CD4
Figure 4.
GS-99-903: Mean (95% CI) Change from Baseline in CD4 Cell
Count (ITT Analysis Set)
500
500
400
400
300
300
200
200
100
100
0
0
BL
8
16
24
32
40
48
56
64
72
80
88
96
120
144
242
237
239
234
Weeks on Study
TDF+3TC+EFV: 299 274 282 275 269 246 264 257 257 257 249 252 252
d4T+3TC+EFV: 301 278 281 280 272 250 270 266 258 258 254 254 248
Source: Module 5.3.5.1, GS-99-903 144-Week CSR; Section 15.3, Week 144, Figure 3.1
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Final
After 144 weeks of double-blind treatment, subjects at selected study sites were offered the
option to continue into a 336-week, open-label, extension phase of Study GS-99-903 in
which all subjects receive the regimen of TDF + 3TC + EFV. Table 32 has additional
information regarding the longer-term data.
For the subset of subjects who continued on the TDF regimen (TDF/TDF group; n = 86) in
the open-label phase, interim analyses demonstrate potent and durable efficacy through
240 weeks of treatment. The percentages of subjects in the TDF/TDF group with plasma
HIV-1 RNA concentrations < 400 copies/mL and < 50 copies/mL at Week 240 (open-label
Week 96) were 87% (75 of 86 subjects) and 83% (71 of 86), respectively (M = F analysis).
Virologic response was maintained in virologically-suppressed subjects who switched from
the d4T regimen to the TDF regimen (d4T/TDF group; n = 85). Following 96-weeks of
open-label treatment with TDF, the percentages of subjects with plasma HIV-1 RNA
concentrations < 400 copies/mL and < 50 copies/mL were 95% (81 of 85 subjects) and 91%
(77 of 85), respectively (M = F analysis).
The immunologic benefits of treatment as demonstrated by increasing CD4 cell count
continued during long-term treatment. For the TDF/TDF group the mean increases from
double-blind baseline at Weeks 144 and 240 were 273 and 421 cells/mm3, respectively. After
the switch from d4T to open-label TDF, the mean increase from open-label baseline at openlabel Week 96 for the d4T/TDF group was 118 cells/mm3.
2.5.4.4.3.
Efficacy in Study M02-418
In Study M02-418, the regimens of FTC + TDF + LPV/r (once or twice daily) demonstrated
potent and durable efficacy during 96 weeks of treatment. No statistically significant
differences were observed between the once daily and twice daily groups for the proportions
of subjects achieving plasma HIV-1 RNA < 50 copies/mL at Weeks 48 or 96. At Week 48,
70% of the subjects in the once daily group and 64% of subjects in the twice daily group
achieved plasma HIV-1 RNA < 50 copies/mL using the ITT (noncompleter=failure
[NC = F]) analysis (Table 8). At Week 96, 57% of the subjects in the once daily group and
53% of subjects in the twice daily group achieved plasma HIV-1 RNA < 50 copies/mL using
the ITT (NC = F) analysis.
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Table 8.
Final
M02-418: Proportion of Subjects with HIV-1 RNA
< 50 Copies/mL at Weeks 48 and 96
FTC + TDF + LPV/r
800/200 mg
Once Daily
Analysis Type
FTC + TDF + LPV/r
400/100 mg
Twice Daily
p-valuea
95% Confidence
Interval for
Difference
Week 48
ITT (NC = F)
81/115
(70%)
48/75
(64%)
0.353
–7.3%, 20.1%
ITT (M = F)
80/115
(70%)
47/75
(63%)
0.324
–6.9%, 20.7%
ITT (LOCF)
91/115
(79%)
54/75
(72%)
0.258
–5.5%, 19.7%
Observed Data
80/89
(90%)
47/54
(87%)
0.600
–8.1%, 13.8%
ITT (NC = F)
66/115
(57%)
40/75
(53%)
0.582
–10.4%, 18.5%
ITT (M = F)
66/115
(57%)
40/75
(53%)
0.582
–10.4%, 18.5%
ITT (LOCF)
88/115
(77%)
53/75
(71%)
0.367
–7.0%, 18.8%
Observed Data
66/74
(89%)
40/44
(91%)
0.765
–12.8%, 9.3%
Week 96
LOCF, last observation carried forward
a
Comparing groups
Source: Module 5.3.5.1, M02-418 CSR, Table 9
In both groups, statistically significant (p < 0.001) decreases in mean plasma HIV-1 RNA
levels were seen as early as the first visit following the baseline evaluation and were
maintained at all subsequent visits through Week 96. The mean decrease from baseline to
Week 48 was 3.14 log10 copies/mL in the once daily group and 3.00 log10 copies/mL in the
twice daily group. The mean decrease from baseline to Week 96 was 3.09 log10 copies/mL in
the once daily group and 3.09 log10 copies/mL in the twice daily group.
Statistically significant (p < 0.001) increases in mean CD4 cell counts in both groups were
observed at all visits. The mean change from baseline to Week 48 was 185 cells/PL in the
once daily group and 196 cells/PL in the twice daily group. The mean change from baseline
to Week 96 was 244 cells/PL in the once daily group and 264 cells/PL in the twice daily
group. No statistically significant differences were observed between the once daily and
twice daily groups in mean change from baseline in CD4 cell counts at any time point.
2.5.4.5.
Efficacy of the FTC/RPV/TDF FDC Tablet
The use of the FTC/RPV/TDF FDC tablet is principally supported by data from the 2 Phase 3
Studies C209 and C215, as follows:
x
Week 48 efficacy data was pooled from the 2 ongoing registrational Phase 3 trials, C209
and C215. The pooled efficacy results from analyses performed when all subjects
completed 48 weeks of treatment or discontinued earlier from these 2 Phase 3 trials (up to
the cut-off date of 01 February 2010 for C209 and 28 January 2010 for C215) are
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Final
presented in Section 2.5.4.5.1. The trials enrolled treatment-naive subjects. These pooled
data provide the key efficacy results for TMC278 in this patient population. A pooling of
the efficacy results of the 2 Phase 3 trials C209 and C215 was performed and a
meta-analysis was performed in accordance with the ICH E9 guideline (Note for
guidance on statistical principles for clinical trials. CHMP/ICH/363/96, 1996).
Combining the efficacy results from the 2 trials was deemed appropriate based on the
similarity in the trial designs. The main purposes of the pooled efficacy analysis were to
determine a more precise overall treatment effect, to evaluate efficacy in prespecified
relevant subgroups, to compile comprehensive data for the determination of the resistance
profile of TMC278, and to gain a better understanding of any
pharmacokinetic/pharmacodynamic relationship. Noninferiority of TMC278 versus
control (EFV) was to be established in each of the 2 Phase 3 studies separately. Any
clinically relevant differences between the trials are discussed.
x
A subanalysis of the virologic outcomes using pooled data for subjects receiving RPV or
EFV in combination with FTC/TDF was performed and is presented in Section 2.5.4.5.1.
Trials C209 and C215 were of an adequate design and duration, as recommended in
applicable regulatory guidance, to establish the efficacy and safety of the antiretroviral
regimens under investigation for the treatment of HIV-1 infection. The main study design
and population characteristics are summarized in Table 9.
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Table 9.
Principal Clinical Studies that Support Use of the FTC/RPV/TDF FDC Tablet – Design and Population
Characteristics
Study
C209
(ECHO)
Final
Design
Phase 3, randomized,
double blind,
double-dummy,
active-controlled
international trial
Population
HIV-1 infected,
treatment-naive
subjects
Treatment
Regimens
(Formulation F
Number)a
TMC278
25 mg once daily
(F006) (n = 346)
Or
EFV 600 mg once
daily
(n = 344)
No. of
Subjectsb
690
Duration
Demographics
96 weeksc
Ongoing
Male 78.7%
White 60.9
Mean age 37years
Study Entry (median)
Viral Load: TMC278 Group
= 94,950 copies/mL;
Control Group = 105,000
copies/mL
CD4 count: TMC278 Group
= 240 cells/PL; Control
Group = 257 cells/PL
Both groups
receive a fixed
background
regimen of
FTC/TDF
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Study
C215
(THRIVE)
Design
Phase 3, randomized,
double blind,
double-dummy,
active-controlled
international trial
Population
HIV-1 infected,
treatment-naive
subjects
Final
Treatment
Regimens
(Formulation F
Number)a
TMC278
25 mg once daily
(F006) (n = 340)
Or
EFV 600 mg once
daily
(n = 338)
No. of
Subjectsb
678
Duration
96 weeksc
Ongoing
Demographics
Male 72.9%
White 60.7
Median age
36 years
Study Entry (median)
Viral Load: TMC278 Group
= 83,950 copies/mL;
Control Group = 102,500
copies/mL
CD4 count: TMC278 Group
= 263 cells/PL; Control
Group = 263 cell/PL
Both groups
receive a
background
regimen of 2
investigatorselected N(t)RTIs
(ABC/3TC;
AZT/3TC or
FTC/TDF)
a
b
c
Oral film-coated tablets
Subjects randomized and treated
This Clinical Overview includes data up to and including the Week 48 primary analysis time point
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2.5.4.5.1.
Final
Subanalysis of the Virologic Outcomes using Pooled Data for Subjects
Receiving RPV or EFV in Combination with FTC/TDF
In the Phase 3 RPV trials, the investigational ARV treatment (TMC278 or EFV as control)
had to be administered in combination with a background regimen consisting of 2 N(t)RTIs.
As defined in the protocol, all subjects in trial C209 took FTC/TDF as their background
regimen. In trial C215 the background regimen consisted of 2 investigator-selected N(t)RTIs:
the majority of subjects took FTC/TDF (approximately 60%), whereas the remaining subjects
in this trial took AZT/3TC (approximately 30%) or ABC/3TC (approximately 10%). As a
result, most subjects in the pooled Phase 3 analysis (approximately 80%) took FTC/TDF as
their background regimen, in both treatment groups. A subanalysis of the virologic outcomes
using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF was
performed.
Treatment outcomes through 48 weeks for subjects who received FTC/TDF (N = 1096) in
C209 and C215, are presented in Table 10 (TLOVR analysis) and Table 11 (Snapshot
analysis). The TLOVR and Snapshot algorithms are described in Module 2.7.3.2.6. Virologic
response parameters for the subanalysis using pooled data for subjects receiving RPV or EFV
in combination with FTC/TDF were consistent with results from the overall pooled analysis
for C209 and C215.
In the pooled ITT population for the FTC/TDF subset, the difference in virologic response
(viral load < 50 copies/mL, TLOVR; Table 10) between the TMC278 + FTC/TDF and
control groups was 1.0 (95% CI, í3; 6). The lower limit of the 95% CI of the difference
between the treatment groups was well above í12% and í10%, therefore, noninferiority of
TMC278 versus control was established at the 12% and 10% noninferiority margins.
Table 10.
Virologic and Immunological Outcomes of Randomized
Treatment at Week 48 (TLOVR Analysis)
RPV + FTC/TDF
N = 550
EFV + FTC/TDF
N = 546
HIV-1 RNA < 50 copies/mL (TLOVRa)b
83.5% (459/550)
82.4% (450/546)
Mean Change from Baseline in CD4 Cell
Count (cells/mm3)
+193
+182
N = total number of subjects per treatment group
a
TLOVR = time to loss of virologic response (ITT population)
b The difference of response rate is í3% to 6% (95% CI) using normal approximation
Source: 2.7.3, Table 60 and Table 68
Eighty-three percent of the subjects in the RPV + FTC/TDF arm and 81% of the subjects in
the EFV + FTC/TDF arm achieved plasma HIV-1 RNA < 50 copies/mL by Week 48
(Snapshot analysis; Table 11). The difference of response rate was í3% to 6% (95% CI).
Therefore, RPV in combination with FTC/TDF has been shown to be noninferior in
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Final
achieving HIV-1 RNA < 50 copies/mL when compared to EFV in combination with
FTC/TDF.
Table 11.
Rilpivirine Studies C209 and C215 (Pooled Data for Subjects
Receiving RPV or EFV in Combination with FTC/TDF): Virologic
Outcome of Randomized Treatment at Week 48 (Snapshot
Analysis)
RPV+ FTC/TDF
N = 550
EFV + FTC/TDF
N = 546
83%
81%
13%
8%
Discontinued study due to adverse event or deathc
2%
7%
Discontinued study for other reasonsd
2%
4%
< 1%
< 1%
Virologic Outcomea
Virologic success HIV-1 RNA < 50 copies/mL
b
Virologic failure
No virologic data at Week 48 window
Reasons
Missing data during window but on study
a
The snapshot analysis was based on the last observed viral load data within the Week 48 window
(Week 4454)
Includes subjects who had t 50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss
of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at
the time of discontinuation had a viral value of t 50 copies/mL, and subjects who had a switch in background regimen
that was not permitted by the protocol.
c
Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in
the Week 48 window.
d Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy,
e.g., withdrew consent, loss to follow-up, etc.
Source: Module 2.7.3, Appendix 2.7.3.6.6
b
2.5.4.5.2. Baseline Genotype and Phenotype Characteristics
Both at screening and baseline, the genotypic sensitivity to the NNRTIs and N(t)RTIs was
determined by the vircoTYPE HIV-1 test.
For simplicity, ‘baseline’ genotype refers to the determinations at ‘baseline and/or
screening’, unless indicated otherwise.
Subjects with 1 or more NNRTI resistance-associated mutations (RAMs), from the list
defined in the protocol exclusion criteria, on their screening (or historical) genotype were not
eligible for participation in the Phase 3 trials. The data on screen failures are presented in
Module 2.7.3.3.3.4.1.1, Table 28. The genotype data obtained at screening confirmed that the
subjects enrolled into the trials had no NNRTI RAMs according to the protocol exclusion list
with 2 exceptions who were categorized as protocol violators. In addition, at screening,
2 subjects had mutation E138A, which was added to the protocol exclusion list only after
these subjects were enrolled and started treatment.
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2.5.4.5.2.1.
Final
Genotypic and Phenotypic Sensitivity to NNRTIs at Baseline
Since not all known NNRTI RAMs were covered by the protocol exclusion criteria list,
13.5% of all randomized and treated subjects had 1 or 2 NNRTI RAMs at baseline according
to the Extended NNRTI RAMs list. The distribution was well balanced between the
2 treatment groups and did not seem to affect phenotypic susceptibility to the regimen
NNRTI.
No relevant differences were noted between the treatment groups or between the trials either
for the total number of NNRTI RAMs or for the presence of specific NNRTI mutations.
Based on phenotypic sensitivity analyses to ARV treatments using Antivirogram, the
median TMC278 fold change (FC) in the TMC278 group at baseline was 1.10 (range 0.2-6.1)
and 1.20 (range 0.2–5.5) in the control group. The median FC values at baseline for the other
NNRTIs (EFV, ETR, and NVP) were all below the respective biological cut-offs (BCOs).
Nearly all subjects were sensitive to TMC278 (99.3%) and to EFV (99.3%). For the TMC278
group, 99.4% of subjects were sensitive to TMC278 and 99.4% to EFV. Comparable results
were observed for the control group (99.3%, 99.2%, respectively).
2.5.4.5.2.2.
Genotypic and Phenotypic Sensitivity to N(t)RTIs at Baseline
The number of subjects with at least 1 N(t)RTI RAM from the International AIDS
Society-United States of America (IAS-USA) list {13428} at baseline was 26 (3.8%) in the
TMC278 group and 15 (2.2%) in the control group. At the individual trial level, more
subjects had N(t)RTI RAMs in the TMC278 group (6.2%) than in the control group (2.1%)
in C215, whereas the proportion of subjects with N(t)RTI RAMs was comparable in the
TMC278 group (1.4%) and the control group (2.3%) in C209. The most prevalent N(t)RTI
RAMs from this list at baseline in the pooled analysis were M41L and A62V (each in
15 subjects [1.1%]) with no apparent difference between the treatment groups.
The median FC values for each N(t)RTI observed at baseline were below their respective
BCOs or clinical cut-offs (CCOs) (for N(t)RTI BCOs and CCOs, refer to Module
2.7.3.3.6.1.3, Table 73).
For the TMC278 group in the pooled analysis, the phenotypic sensitivity to ARV treatments
determined using Antivirogram at baseline indicated that most subjects (93.7%) were
sensitive to the 7 N(t)RTIs assessed. Comparable results were observed for the control group
in the pooled analysis (94.5%, respectively).
At baseline, phenotypic sensitivity indicated that a large proportion of subjects (95.5%) was
sensitive to both background N(t)RTIs selected by the investigator based on the screening
vircoTYPE report, with no differences between the treatment groups. No differences in
sensitivity to N(t)RTIs (for the allowed background N(t)RTIs in each trial) were observed
between the treatment groups.
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Final
It is important to note that nearly all randomized and treated subjects (99.9%) were sensitive
to both their background N(t)RTIs (according to the vircoTYPE HIV-1) at screening since
this was a selection criterion and only one subject did not comply with this requirement and
was classified as a protocol violator. The difference between screening and baseline is small
and mostly due to the differences in the way FC values were calculated by these assays
(vircoTYPE HIV-1 at screening for inclusion into the trial, and Antivirogram at baseline
for the analysis) (Report TMC278-C204-C215-C904-W48-AVMR).
No subjects were resistant to ABC or to FTC at baseline. For 3TC, 2 subjects (0.3%) in the
TMC278 group and none in the control group were resistant at baseline. For AZT, 5 subjects
(0.8%) in the TMC278 group and 2 (0.3%) in the control group were resistant at baseline,
and for TDF, resistance was observed in 32 subjects (4.8%) in the TMC278 group and
33 (5.0%) in the control group. In all the cases where resistance was detected, the FC values
observed were marginally above the BCO/CCO.
2.5.4.5.3.
Efficacy in Studies C209 and C215
This section provides an overview of the 48-week primary analysis of the efficacy results for
the Phase 3 trials C209 and C215 with focus on the pooled analysis, highlighting any
clinically relevant differences between the studies.
The efficacy results of the Week 48 primary analyses were generally consistent across both
Phase 3 trials. In the individual trials, the difference in virologic response rates between the
TMC278 and the control groups was similar. Both trials individually and independently
demonstrated noninferiority of TMC278 versus control at the 12% and 10% noninferiority
margins.
For details, refer to Module 2.7.3.2.6. Full results for the individual trials are available in the
individual CRRs (Module 5.3.5.1, TMC278-C209-CRR and Module 5.3.5.1,
TMC278-C215-CRR).
For resistance determination data from the pooled Phase 3 analysis, see Section 2.5.4.6.2.
Pharmacokinetic/pharmacodynamic relationships based on observed data in the Phase 3 trials
were evaluated for the relationship between pharmacokinetic parameters and efficacy; an
overview is presented in Section 2.5.3.3.1.2.
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2.5.4.5.3.1.
Final
Primary and Secondary Efficacy Parameters
2.5.4.5.3.1.1.
Virologic Response
The primary efficacy parameter was the proportion of subjects with plasma viral load
< 50 copies/mL at Week 48 according to the TLOVR imputation algorithm (FDA Guidance
for industry, antiretroviral drugs using plasma HIV RNA Measurements - Clinical
considerations for accelerated and traditional approval, prepared by the Division of Antiviral
Drug Products: Office of Drug Evaluation IV in the Center for Drug Evaluation and Research
(CDER), Appendix B; October 2002).
Figure 5 presents the proportion of subjects demonstrating virologic response
(< 50 copies/mL, TLOVR) for the ITT population.
Figure 5.
Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials:
Proportion of Virologic Responders (< 50 HIV-1 RNA copies/mL,
TLOVR) at Week 48
Source: Module 2.7.3.3.6.1.1, Figure 21
The proportion of subjects that achieved a viral load < 50 copies/mL according to the
TLOVR algorithm at Week 48 was similar between the TMC278 group (84.3%) and the
control group (82.3%).
Statistical comparison using a logistic regression model showed a predicted difference
[95% CI] in virologic response (viral load < 50 copies/mL, TLOVR) at Week 48 between the
pooled TMC278 and control treatment groups of 1.6 [-2.2; 5.3] (p-value < 0.0001),
demonstrating noninferiority at both the 12% (primary endpoint) and 10% (secondary
endpoint) margins. Superiority of TMC278 compared to control was not established.
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Final
In both trials C209 and C215 individually, there was no notable difference in response rate
(< 50 copies/mL, TLOVR, ITT population) between the TMC278 group and the control
group (82.9% vs 82.8% in C209, and 85.6% vs 81.7% in C215, see Figure 5) and the primary
endpoint of noninferiority at the 12% margin was met in each trial independently. Based on
the ITT and per protocol (PP) population, noninferiority was also demonstrated at the 10%
margin in both trials.
The proportion of virologic responders seen in the control group in the Phase 3 trials was
greater than or comparable to that seen for the same EFV-based combination antiretroviral
therapies (ARTs) in previous trials. In light of this and the noninferiority of TMC278 to
control established in the Phase 3 trials, the efficacy of TMC278 in respect of the proportion
of virologic responders can be considered comparable to previously published data for EFV
{15040}, {15966}, {15968}, {12654}.
The proportions of virologic responders between the TMC278 and control groups was similar
when virologic response was defined as < 200 copies/mL or < 400 copies/mL (TLOVR).
The proportion of virologic responders at Week 48 with viral load < 50 copies/mL according
to the snapshot analysis, together with reasons for nonresponse, is presented in Table 12 for
the ITT population. The snapshot analysis was in line with the TLOVR pooled analysis data,
with virologic response rates of 82.5% in the TMC278 group and 80.1% in the control group,
confirming that noninferiority of TMC278 compared with control was demonstrated with
maximum allowable differences of 12% and 10% (predicted difference [95% CI] in virologic
response of 2.0 [-2.1; 6.1]) (both with p < 0.0001, logistic regression model).
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Table 12.
Final
Phase 3 Trials C209, C215, and the Pooled Phase 3 Trials:
Virologic Outcome (< 50 HIV-1 RNA Copies/mL, Snapshot) at
Week 48
C209
C215
Pooled
Snapshot Outcome at Week 48,
n (%)
TMC278
N = 346
Virologic Response HIV RNA
< 50 copies/mL
285 (82.4) 281 (81.7)
Nonresponders
61 (17.6)
63 (18.3)
59 (17.4) 73 (21.6) 120 (17.5) 136 (19.9)
47 (13.6)
24 (7.0)
41 (12.1) 38 (11.2)
88 (12.8)
62 (9.1)
Ongoing and HIV RNA
t 50 copies/mL
17 (4.9)
13 (3.8)
17 (5.0)
15 (4.4)
34 (5.0)
28 (4.1)
Virologic failure leading to
discontinuation
20 (5.8)
4 (1.2)
12 (3.5)
8 (2.4)
32 (4.7)
12 (1.8)
Discontinued due to other reason
and last available HIV RNA
t 50 copies/mLb
10 (2.9)
7 (2.0)
8 (2.4)
9 (2.7)
18 (2.6)
16 (2.3)
0
0
4 (1.2)
6 (1.8)
4 (0.6)
6 (0.9)
14 (4.0)
39 (11.3)
18 (5.3)
35 (10.4)
32 (4.7)
74 (10.9)
Discontinued due to AE/deathc
6 (1.7)
25 (7.3)
9 (2.6)
24 (7.1)
15 (2.2)
49 (7.2)
Discontinued due to other reason
and last available HIV RNA < 50
copies/mL (or missing)b
5 (1.4)
12 (3.5)
8 (2.4)
11 (3.3)
13 (1.9)
23 (3.4)
Missing data during window but
on study
3 (0.9)
2 (0.6)
1 (0.3)
0
4 (0.6)
2 (0.3)
Virologic Failurea
Switch in background N(t)RTIs not
permitted by protocol
No Viral Load Data in Week 48
Window
Control
N = 344
TMC278 Control
N = 340 N = 338
281
(82.6)
265
(78.4)
TMC278
N = 686
Control
N = 682
566 (82.5) 546 (80.1)
N = number of subjects per treatment group; n = number of observations
Includes subjects who had t 50 copies/mL in the Week 48 window, subjects who discontinued early due to lack or loss
of efficacy, subjects who discontinued for reasons other than AE, death or lack or loss of efficacy and at the time of
discontinuation had a viral load value of t 50 copies/mL (or missing), and subjects who had a switch in background
regimen that was not permitted by the protocol.
b Includes subjects who discontinued for reasons other than AE, death, or lack or loss of efficacy, e.g., withdrew consent,
loss to follow-up, etc.
c
Includes subjects who discontinued due to AE or death if this resulted in no on-treatment virologic data in the Week 48
window. No subjects died in trial C209 and 1 subject in the TMC278 group and 3 subjects in the control group died in
trial C215.
Note: The snapshot analysis was based on the last observed viral load data within the Week 48 window (Week 44 - 54).
a
A tabulation of virologic outcome for the viral load < 50 copies/mL using the TLOVR
analysis is provided in Module 2.7.3.3.6.1.1, Table 63.
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Table 12 also presents the categorization by reason of nonresponse according to the snapshot
analysis for the ITT population. In the TMC278 group, 12.8% of subjects were virologic
failures versus 9.1% of subjects in the control group. Among these, a greater proportion of
subjects discontinued due to virologic failure in the TMC278 than in the control group (4.7%
versus 1.8%, respectively) according to the snapshot analysis. For the other categories of
virologic failure, the proportions were similar between treatment groups. The proportions of
treatment failures with missing viral load data in the Week 48 window were similar per
treatment group across the individual Phase 3 trials; in both trials, there were a smaller
proportion of subjects in the TMC278 group than in the control group. Of the subjects who
were treatment failures due to missing viral load data in the Week 48 window, the most
frequent reason for discontinuation was due to AE/death in both trials, with smaller
proportions of subjects discontinuing for this reason in the TMC278 group than in the control
group.
In the pooled analysis, the results of different sensitivity analyses confirmed that the primary
analysis results for virologic response defined as the proportion of subjects with confirmed
< 50 copies/mL were robust and consistent across different populations. For all analyses, the
lower limit of the 95% CI of the difference between the treatment groups was consistently
and considerably above -12% demonstrating noninferiority of TMC278 versus control.
Sensitivity analyses also showed noninferiority of TMC278 versus control at the
10% margin.
When comparing with the virologic response at Week 48 in the Phase 2b trial, it can be
concluded that the virologic response rates in the Phase 2b and the Phase 3 trials are highly
consistent. Overall, the virologic response rates (< 50 copies/mL TLOVR) at Week 48 in the
Phase 3 pooled analysis (84.3% and 82.3% in the TMC278 and control groups, respectively)
were similar to those in the Phase 2b trial at Week 48 (80.6% and 80.9% with TMC278 and
control, respectively).
2.5.4.5.3.1.2.
Virologic Response over Time
In the Phase 3 pooled analysis, the proportion of responders (viral load < 50 copies/mL,
TLOVR) over time in the TMC278 and control groups were similar up to Week 48 with
overlapping curves.
2.5.4.5.3.1.3.
Time to Response and Time to Treatment Failure
No clear difference between the 2 treatment groups was noticed from the Kaplan-Meier
curves for time to response (< 50 copies/mL, TLOVR) in the pooled analysis. Some
separation between the curves for the 2 treatment groups was seen from Week 18 onwards
when around 75% cumulative proportion of responders was reached, but this difference
disappeared from approximately Week 36 onwards. By the latter time points, the cumulative
proportions of responders were similar between the treatment groups in the pooled analysis.
These findings indicate that subjects took somewhat longer in the TMC278 group to reach
virologic suppression.
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A Cox proportional hazards model for time to response (< 50 copies/mL, TLOVR)
comparing treatments adjusted for baseline viral load showed significant effects of baseline
viral load and treatment in the pooled analysis (p < 0.0001 and p = 0.0001, respectively).
Subjects in the TMC278 group took longer to reach virologic response than those in the
control group and subjects with a higher baseline viral load took longer to respond in both
treatment groups.
Subgroup analysis of time to virologic response by baseline viral load category indicated that
the median time to response was approximately 12 weeks for the low baseline viral load
category ( 100,000 copies/mL), approximately 16 weeks for the
> 100,000 to 500,000 copies/mL category, and to between 18 and 24 weeks for the highest
viral load category (> 500,000 copies/mL). The median time to response was similar for both
treatment groups in the low and intermediate baseline viral load categories, while in the
highest viral load category the median time to response was longer in the TMC278 group
than in the control group. These results should be interpreted with caution, however, due to
the small numbers of subjects in the highest viral load subgroup.
Although more subjects in the control group were never suppressed, the rate of treatment
failures between treatment groups was similar. Kaplan-Meier curves and Cox proportional
hazards models (TLOVR and TLOVR nonvirologic failure [non-VF] censored analyses)
indicated that treatment group had no effect on time to treatment failure in the pooled
analysis, i.e., subjects were experiencing treatment failure at similar rates between the
treatment groups. A statistically significant effect of baseline viral load was seen in both
treatment groups (p < 0.0001), i.e., for subjects with lower baseline viral load, it took longer
to reach treatment failure.
Subgroup analyses of time to treatment failure indicated that greater proportions of virologic
failures were seen with increasing baseline viral load category, and this was seen in both
treatment groups in the pooled analysis.
2.5.4.5.3.1.4.
Immunology
Both treatment groups showed a reconstitution of absolute and relative (%) CD4+ cell count
at Week 48. The mean change from baseline in imputed absolute CD4+ cell count at Week 48
was 192.1 cells/PL; 95% CI [181.30; 202.94] in the TMC278 group and 176.2 cells/PL;
95% CI [164.63; 187.76] in the control group. Although in the pooled analysis, this
difference in favor of TMC278 was statistically significant (p = 0.0263, analysis of
covariance [ANCOVA]). The difference between the treatment groups in increase from
baseline in CD4+ cell count did not reach statistical significance in the individual trials.
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2.5.4.5.3.2.
Final
Subgroup Analysis of Factors Influencing Efficacy
Subgroup analyses of factors influencing efficacy presented in this section showed some
differences in virologic response. Limitations of these univariate subgroup analyses should,
however, be acknowledged when interpreting the data and differences. In particular, data
need to be interpreted with caution for subgroups that are small in sample size.
A more robust multivariate analysis using generalized additive models (GAM) to evaluate
the impact of various potential predictive factors on efficacy parameters is presented in
Section 2.5.4.5.3.4.
2.5.4.5.3.2.1.
Virologic Response
Virologic response (viral load < 50 copies/mL, TLOVR) by subgroups is displayed in
Table 13 for the Phase 3 pooled analysis.
Virologic response was also analyzed by patient-reported adherence for the treatment NNRTI
for the overall treatment period (refer to Module 2.7.3.3.6.1.3, Table 70).
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Table 13.
Final
Rilpivirine Studies C209 and C215 (Pooled Data): Proportion of
Virologic Responders (< 50 HIV-1 RNA Copies/mL, TLOVR) at
Week 48 by Subgroups
TMC278
Parameter, n(%)
Control
N
n (%)
N
n (%)
Male
518
438 (84.6)
519
425 (81.9)
Female
168
140 (83.3)
163
136 (83.4)
White
420
359 (85.5)
410
340 (82.9)
Black/African American
165
124 (75.2)
156
116 (74.4)
Asian
78
74 (94.9)
97
90 (92.8)
Other
14
13 (92.9)
12
11 (91.7)
Region 1: USA, Canada, Europe, Australia
379
309 (81.5)
347
271 (78.1)
Region 2: Africa
51
42 (82.4)
69
55 (79.7)
Region 3: Asia
106
96 (90.6)
112
103 (92.0)
Region 4: Latin America
150
131 (87.3)
154
132 (85.7)
B
485
405 (83.5)
462
376 (81.4)
C
76
65 (85.5)
89
70 (78.7)
CRF01_AE
76
69 (90.8)
70
64 (91.4)
Other
49
39 (79.6)
61
51 (83.6)
Gender
Race
Region
Clade
Baseline Viral Load Category, copies/mL
100,000
368
332 (90.2)
330
276 (83.6)
> 100,000 - 500,000
249
198 (79.5)
270
223 (82.6)
> 500,000
69
48 (69.6)
82
62 (75.6)
+
Baseline CD4 Count Category, cells/PL
< 50
34
20 (58.8)
36
29 (80.6)
t 50 - < 200
194
156 (80.4)
175
143 (81.7)
t 200 - < 350
313
272 (86.9)
307
253 (82.4)
t 350
144
130 (90.3)
164
136 (82.9)
FTC/TDF
550
459 (83.5)
546
450 (82.4)
AZT/3TC
101
88 (87.1)
103
83 (80.6)
ABC/3TC
35
31 (88.6)
33
28 (84.8)
Background Regimen
N = number of subjects per subgroup category; n = number of subjects with virologic response < 50 copies/mL.
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A trend for greater proportions of virologic responders with lower baseline viral load was
seen in both treatment groups. In the 100,000 copies/mL baseline viral load category,
90.2% and 83.6% of subjects in the TMC278 and control groups, respectively, had virologic
response, whereas 69.6% and 75.6% of subjects respectively had virologic response in the
> 500,000 copies/mL category. Similar trends for the influence of high baseline viral load on
virologic response have been reported with other ARV treatments {15873}, {12554},
{14246}, {15869}, {15864}. This pattern was also seen in both individual trials C209 and
C215, although to a much lesser extent in the control group in trial C209. In trial C209, a
smaller proportion of responders was seen in the TMC278 group than the control group in
the > 500,000 copies/mL category (61.8% versus 80.9%), whereas this was not seen in trial
C215 (77.1% versus 68.6%).
The proportion of virologic responders in the TMC278 group in the pooled analysis
increased with increasing baseline CD4+ cell count category, ranging from 58.8% in subjects
with baseline CD4+ cell count < 50 cells/PL to 90.3% in subjects with baseline CD4+ cell
count > 350 cells/PL. There was little variation in the proportion of virologic responders in
the control group with increasing baseline CD4+ cell count. The proportion of virologic
responders in the TMC278 group was greater than control in the t 350 cells/PL
(90.3% versus 82.9%) and the t 200 to < 350 cells/PL categories (86.9 versus 82.4%).
Virologic response was similar in the 2 treatment groups in the t 50 to < 200 cells/PL
category (80.4% versus 81.7%) and lower in the TMC278 group than control (58.8% versus
80.6%) for the < 50 cells/PL category.
While acknowledging the low numbers of subjects (n = 14 and n = 15 in the TMC278 and
control groups, respectively), the response rates in subjects with very high baseline viral load
(> 500,000 copies/mL) and low baseline CD4+ cell count (< 50 cells/PL) were 71.4% in the
TMC278 group and 73.3% in the control group (see Module 2.7.3.3.6.1.3).
Background regimen did not appear to have an effect on virologic response as the
proportions of virologic responders were similar for the different background regimens. The
greatest proportions of virologic responders were seen for the ABC/3TC background regimen
in both treatment groups, but only a small number of subjects were receiving this background
regimen (approximately 5% of the total population in the pooled analysis). The proportions
of subjects with virologic response taking FTC/TDF (the largest subgroup) were similar
across the individual Phase 3 trials.
Male and female subjects responded equally well to the NNRTI treatments in the pooled
analysis. A difference between the trials was seen for gender, with lower proportions of
responders in the TMC278 group for female subjects in the C209 trial, which was not
observed in the C215 trial. In the control group in trial C209, the proportion of responders
was higher in males, while in trial C215 it was higher in females.
Virologic response rates were approximately 75% in Black/African American subjects in
both treatment groups, compared to > 80% in the other races. The highest response rate was
seen in Asian subjects in both treatment groups.
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The proportions of virologic responders per region were lower in Region 1 (USA, Canada,
Europe and Australia) and 2 (Africa) than in Region 3 (Asia) and 4 (Latin America) in both
treatment groups in the pooled analysis. There were a greater proportion of subjects with
virologic response in the TMC278 group in the C215 trial in Region 2 (Africa) (94.7%)
compared to the other regions; however, this was not observed in the C209 trial, where
Region 2 (Africa) (75.0%) had the lowest proportion of virologic responders compared with
the other regions. It should be noted that the number of subjects per treatment group in trial
C215 was not balanced in this region.
For clade B, the most prominent clade in the Phase 3 trials, no difference in virologic
response between treatment groups was observed. Greater proportions of virologic
responders (TLOVR) were seen in the CRF01_AE clade category compared to the other
clades, for both TMC278 and control. However, since the number of subjects in the non-B
clade subgroups was small, results should be interpreted with caution.
In the TMC278 group for the pooled analysis, the proportion of responders in subjects who
did not have hepatitis B/C coinfection at baseline was 85.0%, whereas the proportion of
responders who did have hepatitis B/C coinfection was 73.5%. In the control group, 82.6% of
subjects without hepatitis B/C infection at baseline were responders, and 79.4% of subjects
with infection were responders (Module 5.3.5.3, TMC278-C904-Anal-Eff-Viral/Display
EFF.26).
Analysis of virologic response by adherence, as measured by responses in the patientreported questionnaire Short Form-36 version 2 (SF-36v2), showed that the proportion of
virologic responders was similar between the TMC278 and control group by adherence rate
for the NNRTI, assessed for the overall treatment period. Of those subjects who were at least
95% adherent, the virologic response rates were high and similar between the TMC278 and
control groups (87.6% and 88.4%). Virologic response rates were lower among subjects who
were less than 95% adherent (66.3% on TMC278 and 68.4% on control).
An analysis using generalized additive models (GAM), which evaluated the impact of
various potential predictive factors on efficacy parameters, also demonstrated an important
role of adherence in determining virologic response (see Section 2.5.4.5.3.4).
2.5.4.5.3.3.
Patient-Reported Outcomes
Patient-reported outcomes were evaluated based on the SF-36v2 questionnaire. At baseline,
the subjects in the TMC278 and control group had mean physical component summary
(PCS) and mental component summary (MCS) scores similar to those found in the general
population. Changes in scores from baseline to Week 48 demonstrated improvements over
time in almost all subscales (except for the role physical scale in the control group of study
C215), summary component scores, and SF-6D (a preference based utility index). The
repeated measures analysis indicated no statistically significant difference between the
TMC278 and control group on PCS, MCS, or SF-6D from baseline through Week 48.
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Full details of the results from the SF-36v2 questionnaire are provided in the technical
report (Module 5.3.5.3, TMC278-C904-Report-SF-36).
2.5.4.5.3.4.
Pharmacokinetic/Pharmacodynamic Relationships
All analyses exploring the relationship of TMC278 exposure and efficacy parameters at
Week 48 were done using the TLOVR non-VF censored analysis.
The results described below focus on AUC24h as a measure of TMC278 exposure and plasma
viral load < 50 copies/mL as efficacy parameter. Results are similar for Ctrough, and for
plasma viral load < 400 copies/mL.
Overall, the response rates were high in all the AUC quartiles, ranging from 78.3% to 95.7%.
A lower response rate was observed in the lower quartiles of exposure compared to the
higher quartiles.
Factors potentially associated with virologic response were evaluated in a logistic regression
model including the effects of log10 baseline plasma viral load, exposure (log10-transformed
AUC24h), and background regimen. Both baseline viral load and exposure were significantly
associated (p < 0.001) with a viral load < 50 copies/mL at Week 48 (TLOVR non-VF
censored analysis), while it was independent of the background regimen (p = 0.4774).
Several candidate drug-related factors (i.e., TMC278 AUC24h or C0h, FC for TMC278 at
baseline, having undetectable TMC278 plasma levels at any time during the trial),
treatment-related factors (i.e., background regimen, PSS), disease-related factors
(i.e., baseline viral load, baseline CD4+ cell count), as well as subject-related factors
(i.e., age, weight, gender, race, treatment adherence, and hepatitis B and/or C coinfection)
that may impact the clinical efficacy of TMC278 were assessed using GAM analyses based
on pooled data from the Phase 3 trials (TLOVR non-VF censored). The advantage of GAM
compared to conventional logistic regression is that it is not necessary to make prior
assumptions about the way the candidate factors are included in the model (data-driven rather
than model-driven analysis).
Factors found to be the most predictive for higher virologic response (< 50 copies/mL) in
subjects on TMC278 and a background regimen were in order of importance: 1) higher
adherence, 2) higher TMC278 exposure (C0h), 3) lower baseline viral load, 4) lower
phenotypic FC for TMC278 at baseline, and 5) higher baseline CD4 count. The other
retained prognostic factors (having an undetectable TMC278 plasma concentration at any
time during treatment, and trial) were considered to be less important in explaining the
likelihood of virologic response.
Further details on the GAM analysis results are presented in Module 2.7.2.3.2.4.2.
2.5.4.5.3.5.
Conclusions on Efficacy of the Phase 3 Trial Data
The pooled Phase 3 trials were well-balanced with regards to the demographic and baseline
disease characteristics. Trial C209 had a fixed background regimen of FTC/TDF, and in trial
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C215, the majority of subjects took FTC/TDF as their background regimen; subjects taking
AZT/3TC and ABC/3TC constituted approximately 15% and 5% of subjects, respectively, in
the pooled Phase 3 trials.
Virologic response (< 50 copies/mL, TLOVR) rates were high and consistent between the
individual Phase 3 trials. The proportions of subjects with virologic response in the Phase 3
pooled analysis ITT population were 84.3% and 82.3% in the TMC278 and control groups,
respectively. TMC278 was clearly noninferior to control, well above both the 12% and 10%
margins. Superiority for TMC278 was not demonstrated.
The snapshot analysis confirmed the results of the TLOVR analysis: 82.5% and 80.1% of
subjects in the TMC278 and control groups, respectively, were responders at Week 48.
The different sensitivity analyses on the pooled Phase 3 data confirmed noninferiority of
TMC278 versus control at the 12% level demonstrating robustness of the results.
In both Phase 3 trials, more subjects on TMC278 failed virologically (particularly in C209)
compared to control (both according to snapshot and TLOVR outcome). In contrast, more
subjects on control discontinued from the trial for safety reasons (AE/death) than on
TMC278.
In the Phase 3 pooled analysis (< 50 copies/mL, TLOVR), response rates over time were
similar for the treatment groups and there were no notable differences in response rates over
time between the individual Phase 3 trials. Virologic response parameters for the subanalysis
using pooled data for subjects receiving RPV or EFV in combination with FTC/TDF were
consistent with results from the overall pooled analysis for C209 and C215.
Time to virologic response was slightly longer with TMC278 than with control in the Phase 3
pooled analysis and the individual trials. There were no differences between treatments for
the time to treatment failure in the pooled analysis or either trial.
The mean increase from baseline in imputed absolute CD4+ cell count was 192.1 cells/PL in
the TMC278 group and 176.2 cells/PL in the control group in the pooled analysis. Although
no statistically significant differences were seen in the individual trials for mean change from
baseline in imputed absolute CD4+ cell count, the difference between the TMC278 and
control groups was statistically significant in the pooled analysis.
Response rates were high and comparable to control, irrespective of background regimen and
baseline characteristics such as gender, race, hepatitis coinfection status, or HIV clade.
Background regimen did not have an effect on virologic response for both treatment groups.
Baseline viral load affected the virologic response in both treatment groups, with decreased
response with higher baseline viral load, in line with virologic response to many other ARV
treatments {15873}, {12554}, {14246}, {15869}, {15864}. This effect was more apparent in
the TMC278 subjects, particularly in trial C209. Time to response was similarly affected in
both treatment groups by baseline viral load as was time to (virologic) failure. Baseline CD4+
cell count affected virologic response in the TMC278 group, where a higher virologic
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response was observed with higher CD4+ cell count, whereas a minor influence of the
baseline CD4+ cell count on virologic response was observed in the control group. While
acknowledging the low number of subjects (14 and 15 in the TMC278 and control groups,
respectively), subjects with the lowest baseline CD4+ cell count and the highest baseline viral
load had comparable virologic response rates in the 2 treatment groups.
Adherence (as measured by a patient-reported questionnaire) had an effect on response in
both treatment groups to the same extent, i.e., lower response in subjects who were less
adherent to their regimen.
Performed for TMC278 only, the pharmacokinetic/pharmacodynamic analyses found a
statistically significant effect of baseline viral load and TMC278 exposure on virologic
response. In an analysis using GAM to evaluate the impact of various possible predictive
factors on the efficacy parameters, adherence was found to be the most important predictor of
virologic response (< 50 copies/mL, TLOVR non-VF censored), followed by exposure of
TMC278 and baseline viral load. Also, the predicted virologic response was higher for
subjects with a lower phenotypic FC for TMC278 and a higher CD4+ count at baseline.
There were no notable differences between treatment groups in the patient-reported outcomes
measured by the SF-36v2 questionnaire, at Week 48.
2.5.4.6.
Summary of Clinical Resistance Findings
HIV-1 isolates with reduced susceptibility to each of the individual agents of the
FTC/RPV/TDF FDC tablet have been selected in vitro and identified in clinical isolates from
subjects with virological failure.
Between FTC, RPV, and TFV, no substantial cross-resistance to RPV or TFV has been
demonstrated with the FTC-selected M184V/I mutation. In vitro cross-resistance to FTC has
been shown with the TFV-selected K65R mutation, but there was no cross-resistance to RPV
(TMC278-IV2-AVMR and PC-264-2004). The much higher levels of resistance afforded by
the M184V/I mutation and its greater ease of selection relative to K65R suggest that the
M184V/I mutation will dominate the resistance profile for the combined use of FTC and
TDF in vivo. The selection of the M184V/I mutation prior to selection of the K65R mutation
has been demonstrated in vitro with the combination of FTC and TFV
(Report PC-164-2005). The more common development of the M184V mutation relative to
K65R is also observed in clinical data in subjects treated with TDF and either FTC
(GS-01-934) or 3TC (GS-99-903). NNRTI mutations emerging in HIV-1 under selective
pressure of RPV included combinations of V90I, L100I, K101E, V106A/I, V108I,
E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and M230I/L, where
E138R represented a newly identified NNRTI mutation. A panel of 139 HIV-1 with NNRTI
mutations showed full susceptibility to TFV, and showed full susceptibility to FTC for the
subset of those lacking M184V/I in vitro (Report PC-264-2004). In a pooled analysis for
subjects receiving FTC/RPV/TDF in clinical trials C209 and C215, there were 62 virologic
failure subjects, with resistance information available for 54 of those subjects. The amino
acid substitutions associated with NNRTI resistance that developed most commonly in these
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subjects were: V90I, K101E, E138K/Q, Y181C, V189I, and H221Y. However, the presence
of the substitutions V90I and V189I at baseline did not affect the viral response. The amino
acid substitutions associated with NRTI resistance that developed in 3 or more subjects
during the treatment period were: K65R, K70E, M184V/I, and K219E.
A summary of the principal resistance data relevant to the use of the Truvada and
FTC/RPV/TDF FDC tablets is provided in this section. Resistance data from
Studies GS-01-934, GS-99-903, M02-418, C209, and C215 are presented. Pertinent results
are reflected in the proposed FTC/RPV/TDF prescribing information.
Resistance data for the following supportive studies are described in Module 2.7.3.3.5.3:
x
FTC-301A: Module 2.7.3.3.5.3.1
x
GS-98-902: Module 2.7.3.3.5.3.2
x
GS-99-907: Module 2.7.3.3.5.3.3
Resistance data for the RPV supportive study TMC278-C204 (Phase 2b) is described in
Module 2.7.3.2.2.2.
2.5.4.6.1.1.
Established Resistance Profiles
Emtricitabine-resistant isolates of HIV-1 have been selected in vitro {1794}. Reduced
susceptibility is associated with the M184V/I mutation of the RT gene which also confers
cross-resistance to 3TC, zalcitabine (ddC), and to abacavir (ABC) when present with K65R
or L74V/I. Emtricitabine remains active in vitro against laboratory and clinical strains of
HIV-1 with mutations associated with reduced susceptibility to thymidine analogs, ddI
(L74V), and NNRTIs (Report 11148 and TMC278-IV1-AVMR and TMC278-IV2-AVMR).
Emtricitabine-resistant isolates of HIV-1 with the M184V/I mutation were recovered from
some subjects treated with FTC in combination with other antiretroviral agents in clinical
studies (FTC-301A, FTC-302, FTC-303). These viruses were shown to be phenotypically
resistant to inhibition by FTC and 3TC but remained sensitive to inhibition by ddI, ZDV,
d4T, TFV, and abacavir ( 3-fold change in EC50).
In vitro selection experiments performed at high multiplicity of infection (MOI) showed that
TMC278 was capable of inhibiting viral replication at concentrations where first-generation
NNRTIs fail to do so. The rate of in vitro selection of TMC278-resistant strains at low MOI
was comparable among HIV-1 group M subtypes. The NNRTI mutations emerging in HIV-1
under selective pressure of TMC278 included combinations of V90I, L100I, K101E,
V106A/I, V108I, E138G/K/Q/R, V179F/I, Y181C/I, V189I, G190E, H221Y, F227C, and
M230I/L, where E138R represented a newly identified NNRTI mutation.
In vitro, TFV selected strains of HIV-1 with mutations at K65R that showed reduced
susceptibility to TFV {2078}. The K65R mutation also showed reduced susceptibility to
abacavir, ddI, FTC, 3TC, and ddC in vitro {2141}, {1003}, {1004}, {1793}. Tenofovir shows
reduced activity in vitro and in vivo against strains of HIV-1 with certain patterns of multiple
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thymidine analog mutations {5010}, {5482}. Tenofovir shows slightly increased anti-HIV-1
activity against the M184V mutation selected by abacavir, FTC, and 3TC {2078}, {1649}
and full activity against NNRTI-resistant clinical isolates expressing K103N, Y181C or other
NNRTI mutations (Report P4331-00035, TMC278-IV1-AVMR, TMC278-IV2-AVMR, and
PC-264-2004). In clinical experience, development of K65R has occurred infrequently in
subjects treated with TDF alone or in combination with additional antiretroviral agents from
other drug classes. No subject developed the K65R mutation or any other detectable
sequence changes in RT during up to 4 weeks of monotherapy with TDF (Study GS-97-901).
In treatment-experienced subjects, 3% developed the K65R mutation (Studies GS-98-902
and GS-99-907) after 12 to 96 weeks of combination therapy {4343}. At failure, K65R in the
pooled phase III studies of FTC/RPV/TDF (C209 and C215) in 3 subjects in the RPV group
and 2 subjects in the efavirenz group.
2.5.4.6.1.2.
Resistance Findings in Study GS-01-934
Reverse transcriptase and protease genotypic and phenotypic resistance analyses were
performed at Weeks 48, 96, and 144 for all subjects who had confirmed plasma HIV-1 RNA
! 400 copies/mL at the respective time points while on study drug or after treatment switch.
Through Week 144, 19 subjects from the FTC + TDF group and 31 subjects from the
Combivir group met resistance analysis criteria (Table 14). Genotypic and phenotypic data
were obtained for all 19 subjects in the FTC + TDF group and 29 of the 31 subjects in the
Combivir group. For the remaining 2 subjects in the Combivir group, resistance analyses
failed for technical reasons. For both treatment groups, the most common form of resistance
to develop was resistance to EFV, predominantly the K103N mutation (5% [13/244] in the
FTC + TDF group and 9% [21/243] in the Combivir group). The M184V/I mutation, selected
by FTC or 3TC, developed significantly less frequently in the FTC + TDF group (1%, 2/244)
compared with the Combivir group (4%, 10/243, p = 0.021). Two subjects in the Combivir
group developed thymidine analog mutations, specifically, D67N or K70R mutations in RT.
Through Week 144, no subject developed the K65R mutation that can be selected by TFV.
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Table 14.
Final
GS-01-934: Cumulative Development of Resistance by Week 144
EFV + FTC + TDF, (N = 244)
n (% Total, % With Genotype)
EFV + Combivir, (N = 243)
n (% Total, % With Genotype)
p-valuea
19 (8%)
31 (13%)
0.075
19 (8%)
29 (12%)
0.13
13 (5%, 68%)
22 (9%, 76%)
0.12
13 (5%, 68%)
21 (9%, 72%)
0.16
K103N
8 (3%, 42%)
18 (7%, 62%)
0.046
K101E
3 (1%, 16%)
3 (1%, 10%)
1.0
G190A/S
2 (1%, 10.5%)
4 (2%, 14%)
0.45
Y188C/H
1 (0.4%, 5%)
2 (1%, 7%)
0.63
V108I
1 (0.4%, 5%)
1 (0.4%, 3%)
1.0
P225H
0
2 (1%, 7%)
0.25
2 (1%, 10.5%)
10 (4%, 34.5%)
0.021
TAMsd
0
2 (1%, 7%)
0.25
K65R
0
0
NA
6 (NAe, 32%)
7 (NAe, 24%)
NA
Subject Outcomes
Subjects Analyzed
b
Subjects with Data
Any Resistance
EFV-Resistance
c
M184V/I
Wild-type
a
The p-values are based on the Fisher exact test and the percentage of total.
b Genotypic analysis for 2 subjects in the Combivir group failed for technical reasons.
c
Other EFV resistance mutations included A98G (n = 1), K103E (n = 1), V179D (n = 1), and M230L (n = 1).
d Thymidine analog mutations included D67N (n = 1) and K70R (n = 1)
e
Not applicable (NA) as wild type HIV sequence was not confirmed from subjects with HIV RNA < 400 copies/mL.
Source: Module 5.3.5.1, GS-01-934 CSR, Appendix 14, Virology Listings 1 and 2
2.5.4.6.1.3.
Resistance Findings in Study GS-99-903
During the 144-week treatment period in Study GS-99-903, a similar proportion of subjects
in each of the 2 treatment groups met the failure criteria for resistance analysis: 47 of
299 subjects (16%) in the TDF 3TC EFV group and 49 of 301 subjects (16%) in the
d4T 3TC EFV group. Mutations conferring resistance to the NNRTI class (and
specifically the K103N mutation associated with EFV resistance) were most commonly
observed. Among NRTI-associated resistance mutations, the most common mutation was the
M184V/I associated with 3TC resistance. There were no differences between the treatment
groups in the incidences of these mutations. The majority of virologic failures occurred
within the first 48 weeks of treatment.
During 144 weeks of therapy, the K65R mutation developed in 8 subjects taking the TDF
regimen (7 subjects before Week 48, 1 subject from Weeks 48 to 96, and none after
Week 96) and in 2 subjects taking the d4T regimen (2.7% versus 0.7%: p 0.06). K65R was
always accompanied by resistance to EFV or EFV plus 3TC. Among the 8 subjects who
developed K65R in the TDF 3TC EFV group, successful virologic outcomes were
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achieved upon initiation of second line therapy, with 5 of 8 subjects maintaining
50 copies/mL of HIV-1 RNA through a median of 155 weeks of follow up.
Consistent with the 144-week double-blind period, virologic failure was uncommon during
the open-label phase, and was limited to 2 subjects who continued TDF treatment and no
subjects who switched from d4T to TDF. The K65R mutation was not detected in subjects
who discontinued TDF due to virologic failure.
2.5.4.6.1.4.
Resistance Findings in Study M02-418
In Study M02-418, a total of 17 subjects in the once daily group (15%) and 11 subjects in the
twice daily group (15%) had samples eligible for testing. Resistance testing was successful in
15 subjects in the once daily group and 8 subjects in the twice daily
Three subjects in the once daily group and 1 subject in the twice daily group demonstrated an
M184V/I mutation in reverse transcriptase, indicating the development of FTC resistance. No
reverse transcriptase mutations at positions 41, 44, 62, 65, 67, 69, 70, 74, 115, 118, 210, 215,
or 219, suggestive of selection of NRTI resistance, emerged in any subject.
Six (4 once daily, 2 twice daily) of 23 subjects demonstrated an amino acid substitution in
protease in a postbaseline sample at a position with wild-type amino acid at baseline. Most of
the new amino acid substitutions observed in these 6 subjects were at positions that are
commonly polymorphic. Overall, the evidence suggests that these genotypic changes in
protease were not the direct result of selective pressure of the ARV regimen. No clinically
relevant changes in phenotypic resistance to lopinavir or other PIs were observed, compared
to baseline values, and none of these 6 subjects developed the M184V/I mutation in reverse
transcriptase.
2.5.4.6.2.
Clinical Resistance Findings for C209 and C215
This section describes resistance data for subjects experiencing virologic failure in the
Phase 3 trials.
The resistance determination analysis includes data from any subject experiencing virologic
failure as defined in Module 2.7.3.2.6; this definition of virologic failure is different from
that used for the efficacy outcome analysis to capture as much resistance data as possible.
The results at the failure time point are the most clinically relevant because this is the time at
which the subject should withdraw from treatment, therefore these results are used for
determination of the resistance profile. Failure and end of treatment data were comparable
because the time points were very close to one another.
Emergent RT mutations are those present at failure that are not present at baseline (and/or
screening).
At baseline, given the exclusion criteria applied in the Phase 3 trials (subjects were not to
have NNRTI RAMs from the predefined list of RAMs as per protocol), the vast majority of
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subjects had were susceptible to all NNRTIs. It should be noted that the Extended NNRTI
RAMs list used in the analyses presented in this section contains more mutations (see
Module 5.3.5.4, TMC278-C209-C215-C904-W48-AVMR) as compared to the list used in
the exclusion criteria of the protocols.
2.5.4.6.2.1.
Resistance Determination in the Phase 3 Trials C209 and C215
The focus of the resistance analysis presented in this section is on the pooled data set for the
combined Phase 3 trials with any NRTI backbone (All Subjects) and on the pooled FTC/TDF
subset for the combined Phase 3 trials. It should be noted that the Extended NNRTI RAMs
list used in the analysis presented in this section contains 48 mutations (see
Module 5.3.5.4, TMC278-C209-C215-C904-W48-AVMR) as opposed to the list used in the
exclusion criteria, which contained 39 mutations.
Resistance Determination: Pooled Analysis: All Subjects
In total in the pooled analysis, 72 (10.5%) subjects in the TMC278 and 39 (5.7%) subjects in
the control group in the ITT population met the definition of virologic failure. Of these,
62 (86.1%) of the TMC278 virologic failures and 28 (71.8%) of the control virologic failures
had postdose resistance data at time of failure and were included in the resistance
determination analysis at failure. This resistance analysis focused on these 90 virologic
failures.
The median time to virologic failure was 113.5 days for the TMC278 virologic failures
which was shorter than the 188.0 days for the control virologic failures.
Resistance Determination: FTC/TDF Pooled Subset Analysis
For the pooled FTC/TDF subset analysis, 62 (11.3%) subjects in the TMC278 and 27 (4.9%)
in the control group met the definition of virologic failure. Note that the definitions for these
resistance analyses differ from those used for the efficacy determination. Of the 62 TMC278
virologic failures and 27 control virologic failures, 54 and 20 respectively had postdose
resistance data at the time of failure and were included in the resistance determination
analysis at failure.
2.5.4.6.2.1.1.
Impact of Genotypic and Phenotypic Baseline Characteristics on
Virologic Failure
The baseline characteristics of the virologic failure population were compared to those of the
ITT (VF Excluded) population, i.e., the ITT population from which any subjects complying
with at least one of the 3 virologic criteria (presented in Module 5.3.5.4,
TMC278-C209-C215-C904-W48-AVMR) were excluded.
Evaluation for any over- or under-representation of subjects in the pooled virologic failure
population versus the pooled ITT population (from which virologic failures were excluded
[VF Excluded]) for both treatment groups was conducted according to a number of
demographic and baseline characteristics. Characteristics for which comparable results were
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observed for subjects in the virologic failure and the ITT (VF Excluded) populations in the
pooled analysis, at the individual trial level, and for both treatment groups, included
TMC278 FC, N(t)RTI background regimen, number of sensitive NNRTIs, most prevalent
Extended NNRTI RAMs, HIV-1 clades, and coinfection with hepatitis B/C.
Characteristics for which differences between the 2 populations were observed included
baseline viral load, baseline CD4+ cell count, and race. The differences observed for these
characteristics between the virologic failure and ITT (VF Excluded) populations were
observed in both the TMC278 and control groups. The only difference between treatment
groups was a higher proportion of subjects in the > 100,000 - 500,000 copies/mL baseline
viral load category in the TMC278 virologic failure population compared to the ITT
(VF Excluded) population which was not observed in the control group virologic failure
population.
2.5.4.6.2.1.2.
Emergence of Mutations and Phenotypic Analysis
Emergence of Mutations: Pooled Analysis, All Subjects
The number of virologic failures with treatment-emergent resistance by type and number of
mutations at failure are presented in Table 15 and discussed below. For details, refer to
Module 2.7.3.3.6.1.3, Table 77.
At failure, proportions of virologic failures with any treatment-emergent RT mutation were
comparable in the TMC278 and control groups: 53 (85.5%) versus 25 (89.3%). This also
applies to the Extended NNRTI RAMs: 39 (62.9%) versus 15 (53.6%), respectively, albeit
with a higher proportion of virologic failures with 2 or more treatment-emergent NNRTI
RAMs (Extended list) for the TMC278 than for the control group.
The proportion of virologic failures with at least 1 treatment-emergent IAS-USA
N(t)RT RAM was higher in the TMC278 group (42 subjects, 67.7%) than in the control
group (9 subjects, 32.1%).
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Table 15.
Final
Rilpivirine Studies C209 and C215 (Pooled Data): Virologic
Failures - Number of Treatment-Emergent Reverse Transcriptase
Mutations at Failure
VFs with Postdose Resistance
Data at Failure Analysis, n (%)
Number of mutations
TMC278
N’ = 62
Control
N’ = 28
VFs with any treatmentemergent RT mutation
53 (85.5)
25 (89.3)
VFs with any treatmentemergent Extended NNRTI
RAM
39 (62.9)
15 (53.6)
1
18 (29.0)
10 (35.7)
2
12 (19.4)
3 (10.7)
3
8 (12.9)
1 (3.6)
4
1 (1.6)
0
5
0
1 (3.6)
42 (67.7)
9 (32.1)
1
35 (56.5)
9 (32.1)
2
5 (8.1)
0
3
2 (3.2)
0
VFs with any treatmentemergent IAS-USA N(t)RTI
RAM
N’ = number of virologic failures with postdose resistance data per treatment group; n = number of subjects with mutations;
VF = virologic failure
Note: both baseline and failure are needed to determine treatment-emergent mutations.
Table 16 lists all individual treatment-emergent RT RAMs from the Extended list of
NNRTI RAMs and the IAS-USA list of N(t)RTI RAMs present in at least 2 virologic
failures from the same pooled treatment group at failure. For details, refer to
Module 2.7.3.3.6.1.3, Table 78.
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Table 16.
Final
Rilpivirine Studies C209 and C215 (Pooled Data): Virologic
Failures: Individual Treatment-Emergent Resistance-Associated
Mutations by Type at Failure in at Least 2 Subjects from the
Pooled TMC278 or Control Group
VFs with Postdose Resistance Data at
Failure, n (%)
Individual Mutations
TMC278
N’ = 62
Control
N’ = 28
39 (62.9)
15 (53.6)
E138K
28 (45.2)
0
K101E
8 (12.9)
1 (3.6)
H221Y
6 (9.7)
0
V90I
5 (8.1)
0
Y181C
5 (8.1)
0
V189I
5 (8.1)
0
E138Q
2 (3.2)
0
F227C
2 (3.2)
0
L100I
2 (3.2)
1 (3.6)
V179I
2 (3.2)
0
K103N
0
11 (39.3)
V106M
0
3 (10.7)
Y188C
0
2 (7.1)
42 (67.7)
9 (32.1)
M184I
29 (46.8)
2 (7.1)
M184V
14 (22.6)
6 (21.4)
K65R
3 (4.8)
2 (7.1)
K219E
3 (4.8)
0
A62V
2 (3.2)
0
Y115F
2 (3.2)
0
Treatment-emergent Extended NNRTI
RAMs
Treatment-emergent IAS-USA NRTI
RAMs
N’ = number of virologic failures with postdose resistance data per treatment group; n = number of subjects with mutations;
VF = virologic failure
Note: both baseline and failure are needed to determine treatment-emergent mutations.
The most prevalent treatment-emergent NNRTI and N(t)RTI RAMs at failure in TMC278
virologic failures were E138K (45.2%) and M184I (46.8%), respectively, and these
mutations were usually not found in the control virologic failures, except for 2 subjects with
M184I. Among the control virologic failures, the most frequently emerging NNRTI and
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N(t)RTI RAMs were K103N (39.3%), which was not found in the TMC278 virologic
failures, and M184V (21.4%). M184V was found in a similar proportion of TMC278
virologic failures (22.6%).
Emergence of Mutations: FTC/TDF Pooled Subset Analysis
A subanalysis of the proportion and number of virologic failures with emergent NNRTI and
NRTI mutations per treatment group was performed using pooled data for subjects receiving
RPV (n = 550) or EFV (control; n = 546) in combination with FTC/TDF.
For the pooled FTC/TDF subset analysis, 62 (11.3%) subjects in the TMC278 and 27 (4.9%)
in the control group met the definition of virologic failure. Note that the definitions for these
resistance analyses differ from those used for the efficacy determination. Of the 62 TMC278
virologic failures and 27 control virologic failures, 54 and 20 respectively had postdose
resistance data at the time of failure and were included in the resistance determination
analysis at failure. This resistance analysis of the pooled FTC/TDF subgroup focuses on
these 74 virologic failures.
The FTC/TDF pooled data, at failure are presented in Table 17 and Table 18. The
comparison of the data obtained at failure shows differences in the proportion and number of
virologic failures developing each mutation in the 54 virologic failures in the TMC278 group
and the 20 in the control group.
At failure, the proportions of virologic failures with any treatment-emergent RT mutation
were comparable in the TMC278 and control groups: 46 (85.2%) versus 18 (90%). This also
applies to the Extended NNRTI RAMs: 34 (63%) versus 10 (50%), respectively, albeit with a
higher proportion of virologic failures with 2 or more treatment-emergent Extended NNRTI
RAMs for the TMC278 group than for the control group.
The proportion of virologic failures with at least 1 treatment-emergent IAS-USA NRTI RAM
was higher in the TMC278 group (37 subjects, 68.5%) than in the control group (6 subjects,
30%).
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Table 17.
Final
Virologic Failures: Number of Treatment-Emergent Mutations Failure
Pooled FTC/TDF Subset
Failure
Failure, n (%)
TMC278
N = 54
Control
N = 20
VFs with Any Treatment-Emergent RT
Mutation
46 (85.2)
18 (90.0)
VFs with Any Treatment-Emergent
Extended NNRTI RAMs -- Any
34 (63.0)
11 (55.0)
1
14 (25.9)
7 (35.0)
2
12 (22.2)
2 (10.0)
3
7 (13.0)
1 (5.0)
4
1 (1.9)
0
5
0
1 (5.0)
18 (33.3)
10 (50.0)
1
14 (25.9)
6 (30.0)
2
4 (7.4)
2 (10.0)
3
0
2 (10.0)
37 (68.5)
6 (30.0)
1
31 (57.4)
6 (30.0)
2
4 (7.4)
0
3
2 (3.7)
0
VFs with Any Treatment-Emergent IASUSA NNRTI RAMs -- Any
VFs with Any Treatment-Emergent IASUSA NRTI RAMs -- Anya
N = number of subjects per group; n = number of observations; VF = virologic failure
Note: both baseline and failures are needed to determine treatment-emergent mutations.
a
The RT mutation K65N is not included in the IAS-USA listing of NRTI mutations and was not included in this table.
However, 2 subjects in the TMC278 group developed K65N: one at virologic failure and one at end of treatment; both
showed phenotypic resistance to TFV. No subjects in the control group developed K65N.
Source: Report PC-264-2005 and Module 2.7.3.3.6.1.3, Table 79
Table 18 lists all individual treatment-emergent RT RAMs by type, which were present in at
least 2 virologic failures from the pooled data for all subjects in the TMC278 or control
group at failure.
In the pooled FTC/TDF subset, the amino acid substitutions associated with NNRTI
resistance that developed most commonly in the FTC/TDF subset at virologic failure were:
V90I, K101E, E138K/Q, Y181C, V189I, and H221Y. However, in trials C209 and C215, the
presence of the substitutions V90I and V189I at baseline did not affect the viral response.
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The amino acid substitutions associated with NRTI resistance that developed in 3 or more
patients were: K65R, K70E, M184V/I, and K219E. The M184V/I mutation occurred more
frequently in the TMC278 group compared to the control group (63% in the TMC278 group
versus 20% in the control group) at the failure time point.
Table 18.
Virologic Failures: Emergent Extended NNRTI Mutations, IAS
USA NNRTI Mutations and IAS-USA N(t)RTI Mutations Failure
Failure, n (%)
Failure TMC278
N = 54
Failure Control
N = 20
VFs with Any Emergent RT Mutation
46 (85.2)
18 (90.0)
Treatment-Emergent Extended NNRTI
RAMs -- Any
34 (63.0)
11 (55.0)
E138K
25 (46.3)
0
K101E
7 (13.0)
0
H221Y
6 (11.1)
0
V90I
5 (9.3)
0
Y181C
5 (9.3)
0
V189I
4 (7.4)
0
E138Q
2 (3.7)
0
F227C
2 (3.7)
0
L100I
1 (1.9)
1 (5.0)
V179I
2 (3.7)
0
K103N
0
7 (35.0)
V106M
0
3 (15.0)
Y188C
0
2 (10.0)
18 (33.3)
10 (50.0)
K101E
7 (13.0)
0
V90I
5 (9.3)
0
Y181C
5 (9.3)
0
L100I
1 (1.9)
1 (5.0)
K103N
0
7 (35.0)
V106M
0
3 (15.0)
Y188C
0
2 (10.0)
Treatment-Emergent IAS-USA NNRTI
RAMs -- Any
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Failure, n (%)
Failure TMC278
N = 54
Failure Control
N = 20
Treatment-Emergent IAS-USA NRTI
RAMs -- Anya
37 (68.5)
6 (30.0)
M184I and/or V
34 (63.0)
4 (20.0)
M184I only
23 (42.6)
1 (5.0)
M184V only
6 (11.1)
2 (10.0)
M184V/I mixtures
5 (9.3)
1 (5.0)
3 (5.6)
2 (10.0)
3 (5.6)
0
1 (1.9)
0
b
K65R
K219E
K70E
c
d
N = number of subjects per group; n = number of observations; VF = virologic failure
Virologic failures with missing data at failure are included in the analysis done for end of treatment as long as the genotypic
and phenotypic data at end of treatment were available. Only the NNRTI mutations found in at least 2 virologic failures of
the same group according to the pooled all subjects analysis are presented.
a
The list of NRTI mutations has been expanded from that of the all subjects analysis to highlight potential FTC/TDF
resistance. The RT mutation K65N is not included in the IAS-USA listing of NRTI mutations and was not included in
this table. However, 2 subjects in the TMC278 group developed K65N: one at virologic failure and one at end of
treatment; both showed phenotypic resistance to TFV. Y115 developed in 2 subjects in the TMC278 group at virologic
failure. D67N developed in 2 subjects in the TMC278 group: one at virologic failure and one at end of treatment. No
subjects in the control group developed K65N, D67N, or Y115F.
b Two additional subjects in the TMC278 group developed K65R at the end of treatment time point
c
Two additional subjects in the TMC278 group developed K219E at the end of treatment time point
d Two additional subjects in the TMC278 group developed K70E at the end of treatment time point
Source: Report PC-264-2005 and Module 2.7.3.3.6.1.3, Table 80
Phenotypic Analysis
Phenotypic Analysis: Pooled Analysis – All Subjects
Twenty–five treatment-emergent RT RAMs were found in the virologic failures with a
TMC278 FC > BCO (of 3.7):
x
16 NNRTI RAMs: V90I, L100I, K101E, K101P, K101T, V106A, V108I, E138K,
E138Q, Y181C, Y181I, V189I, H221Y, F227C, F227L, and M230L, and;
x
9 N(t)RTI RAMs: A62V, K65R, D67N, K70E, V75I, Y115F, M184I, M184V, and
K219E.
Some of these mutations were observed in only one TMC278 virologic failure.
Of the 31 virologic failures in the TMC278 group with a TMC278 FC > BCO, 30 (96.8%)
had a combination of at least one NNRTI RAM and one N(t)RTI RAM. Conversely, of the
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31 TMC278 virologic failures with a TMC278 FC BCO, 7 (22.5%) had a combination of at
least one NNRTI RAM plus one N(t)RTI RAM and 18 (58.1%) had no detectable NNRTI or
N(t)RTI RAMs. Of note, the 2 virologic failures who had treatment-emergent NNRTI RAMs
only, had TMC278 FC BCO (these NNRTI RAMs were V179I and V189I/V, which are
both recognized as polymorphisms).
In 37 of 53 TMC278 virologic failures with treatment-emergent RT RAMs at failure, NNRTI
and N(t)RTI RAMs were present in combination.
The most common combination, E138K + M184I, was observed in 21 (39.6%) of the
53 TMC278 virologic failures.
x
A large proportion of the virologic failures with this combination of RT RAMs
(17 subjects, 81.0%) had a TMC278 FC > BCO.
x
The combination E138K + M184I (free of mixtures) was also seen in the absence of any
other NNRTI and/or N(t)RTI RAMs in 6 virologic failures (median TMC278 FC of
6.5 [ranging from 1.6 to 8.8]). Of these, 5 were above the TMC278 BCO.
The combination E138K + M184V (free of mixtures) and in the absence of any other NNRTI
and/or N(t)RTI RAMs) was observed in 3 TMC278 virologic failures (median TMC278 FC
of 2.6 [ranging from 1.8 to 6.5]). Of these, 2 were below the TMC278 BCO.
Of the 62 TMC278 virologic failures with resistance data, 31 (50.0%) had phenotypic
resistance to TMC278 at failure. Among these 31 TMC278 virologic failures resistant to
TMC278, 87.1% were cross-resistant to EFV, 90.3% to ETR, and 45.2% to NVP.
Of the 28 control virologic failures with resistance data, 12 (42.9%) had phenotypic
resistance to EFV at failure. Among the 12 control virologic failures resistant to EFV at
failure, none were cross-resistant to ETR or TMC278 whereas all 12 demonstrated
cross-resistance to NVP.
Resistance to FTC and 3TC was observed in the majority of TMC278 virologic failures
(67.7% and 67.2%, respectively), and to a lesser degree in the control virologic failures
(25.0% and 28.6%, respectively). More than 90.0% of the TMC278 and control virologic
failures retained susceptibility to TDF, ABC, and AZT at failure.
FTC/TDF Pooled Subset Analysis
Table 19 lists all virologic failures from the pooled FTC/TDF subset for TMC278 and control
groups at failure.
Of the 54 subjects with virologic failure and available phenotypic resistance data at virologic
failure, 37 lost susceptibility to FTC, 29 lost susceptibility to RPV, and 2 lost susceptibility to
TDF. Among these subjects, 37 were resistant to lamivudine, 28 were resistant to etravirine,
26 to efavirenz, and 12 to nevirapine. Reduced susceptibility was observed to abacavir and/or
ddI in some cases.
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Table 19.
Final
Virologic Failures: Phenotypic Resistance – Failure
Failure
Virologic Failures with Postdose
Resistance Data at Failure, n (%)
TMC278
N = 54
Control
N = 20
Resistance to NNRTIs
31 (57.4)
9 (45.0)
TMC278
29 (53.7)
0
EFV
26 (48.1)
7 (35.0)
ETR
28 (51.9)
0
NVP
12 (22.2)
9 (45.0)
39 (72.2)
7 (35.0)
Resistance to NRTIs
a
1 (5.0)a
TDF
2 (3.7)
FTC
37 (68.5)
4 (20.0)
3TC
37 (68.5)
b
5 (25.0)
ABC
6 (11.1)
0
ddI
7 (13.0)
0
d4T
3 (5.6)
0
ZDV
2 (3.7)
1 (5.0)
N = number of subjects per group; n = number of observations
a
One additional subject in the TMC278 group and 2 additional subjects in the control group developed phenotypic
resistance to TDF at the end of treatment time point.
b Subject 2150515 had available resistance data at Week 12 and Week 16. The genotype showed K101E/K, V118I/V,
E138E/K, M184I/M/V, E204E/K, and H221H/Y at both time points. The phenotypic assay showed resistance to FTC
and had no data reported for 3TC at Week 12. The Week 16 sample was resistant to both FTC and 3TC. For the
purposes of this analysis, at Week 12 this subject’s 3TC phenotypic data was imputed as “resistant” due to the presence
of M184V/I.
Source: PC-264-2005 and Module 2.7.3.3.6.1.3, Table 81
2.5.4.7.
Conclusions on Resistance Determination
2.5.4.7.1.
Conclusions on Resistance Determination for Emtricitabine
Emtricitabine-resistant isolates of HIV-1 have been selected in vitro {1794}. Reduced
susceptibility is associated with the M184V/I mutation of the RT gene which also confers
cross-resistance to lamivudine and zalcitabine (ddC). Emtricitabine remains active in vitro
against laboratory and clinical strains of HIV-1 with mutations associated with reduced
susceptibility to thymidine analogs, ddI (L74V), and NNRTIs (Report 11148).
Emtricitabine-resistant isolates of HIV-1 with the M184V/I mutation were recovered from
some subjects treated with FTC in combination with other antiretroviral agents in clinical
studies (FTC-301A, FTC-302, FTC-303). These viruses were shown to be phenotypically
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resistant to inhibition by FTC and lamivudine but remained sensitive to inhibition by ddI,
zidovudine, d4T, TDF, and abacavir (< 3-fold change in EC50).
2.5.4.7.2.
Conclusions on Resistance Determination for Rilpivirine
The ARV treatment-naive population included in the C209 and C215 trials was characterized
by the near absence of NNRTI RAMs (based on population sequencing) with the exception
of a limited proportion of patients carrying mutations 90I, 106I, 179I and/or 189I (which
were not excluded based on the protocol list). These 4 mutations had no effect on treatment
response to TMC278 or EFV. At baseline, the vast majority of subjects in each treatment
group were susceptible to their treatment NNRTI and N(t)RTIs.
In total, 72 subjects (10.5%) in the TMC278 group and 39 subjects (5.7%) in the control
group met the definition of virologic failure (VF) adopted for the resistance analysis. The
median time to virologic failure in the TMC278 group was shorter than in the control group
(113.5 days versus 188 days, respectively).
The emergence of at least one NNRTI RAM from the Extended NNRTI list was equally
frequent in the TMC278 and control virologic failures, however, more TMC278 virologic
failures had 2 or more emerging NNRTI RAMs compared to the control group virologic
failures. The most frequent NNRTI RAM emerging in the TMC278 virologic failures was
E138K which was also the most common emerging mutation in the Phase 2b trial C204,
confirming this observation made in the earlier trial. Other NNRTI RAMs emerging in 3 or
more TMC278 virologic failures were K101E, H221Y, and Y181C. In the control group, the
most frequent emerging NNRTI RAM was K103N which was not observed in the TMC278
virologic failures.
The proportion of TMC278 virologic failures with emerging N(t)RTI RAMs was
approximately double that of the virologic failures in the control group in the pooled
analysis. Among TMC278 virologic failures, M184I was the most frequent N(t)RTI RAM
emerging in trial C209, but comparable numbers of virologic failures with emerging M184I
and M184V were observed in trial C215. In the control group virologic failures, M184V was
the most common emerging N(t)RTI RAM.
Fifty percent and 42.9% of TMC278 and control group virologic failures, respectively,
developed phenotypic resistance to their treatment NNRTI. In subjects with TMC278
virologic failure, phenotypic resistance to TMC278 was almost always associated with the
presence of emerging NNRTI and N(t)RTI RAMs. Conversely, only 22.5% of TMC278
virologic failures who remained phenotypically susceptible to TMC278 had a combination of
at least one NNRTI and one N(t)RTI RAM.
In the TMC278 virologic failures, E138K and M184I usually emerged together and were
associated with phenotypic resistance to TMC278 in most cases.
The majority of TMC278 virologic failures with phenotypic resistance to TMC278 were also
resistant to ETR and EFV, while those with phenotypic susceptibility to TMC278 generally
retained susceptibility to both these NNRTIs.
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The resistance findings in C209 and C215 confirmed the resistance observations made in the
Phase 2b trial, from the Week 96 and Week 192 analyses, with the exception of the higher
frequency of the mutation M184I in subjects failing TMC278 which was not previously
noted in Phase 2b.
2.5.4.7.3.
Conclusions on Resistance Determination for Tenofovir DF
In vitro, TFV selected strains of HIV-1 with mutations at K65R that showed reduced
susceptibility to TFV {2078}. The K65R mutation also showed reduced susceptibility to
abacavir, ddI, FTC, lamivudine, and zalcitabine in vitro {2141}, {1003}, {1004}, {1793}.
Tenofovir shows reduced activity in vitro and in vivo against strains of HIV-1 with certain
patterns of multiple thymidine analog mutations {5010}, {5482}. Tenofovir shows slightly
increased anti-HIV-1 activity against the M184V mutation selected by abacavir, FTC, and
lamivudine {2078}, {1649} and full activity against NNRTI-resistant clinical isolates
expressing K103N, Y181C and other RPV-resistant HIV-1 (Reports P4331-00035 and
PC-264-2004). In clinical experience, development of K65R has occurred infrequently in
subjects treated with TDF alone or in combination with additional antiretroviral agents from
other drug classes. No subject developed the K65R mutation or any other detectable
sequence changes in RT during up to 4 weeks of monotherapy with TDF (Study GS-97-901).
In treatment-experienced subjects, < 3% developed the K65R mutation (Studies GS-98-902
and GS-99-907) after 12 to 96 weeks of combination therapy {4343}. At failure, K65R in the
pooled Phase 3 studies of FTC/RPV/TDF (C209 and C215) in 3 subjects in the RPV group
and 2 subjects in the efavirenz group.
2.5.4.7.4.
Conclusions on Resistance Determination for the FTC/RPV/TDF FDC
Tablet
In a pooled analysis for subjects receiving FTC/RPV/TDF in clinical trials C209 and C215,
there were 62 virologic failure subjects, with resistance information available for 54 of those
subjects. The amino acid substitutions associated with NNRTI resistance that developed most
commonly in these subjects were: V90I, K101E, E138K/Q, Y181C, V189I, and H221Y.
However, the presence of the substitutions V90I and V189I at baseline did not affect the viral
response. The amino acid substitutions associated with NRTI resistance that developed in
3 or more subjects during the treatment period were: K65R, K70E, M184V/I, and K219E.
Of the 54 subjects with virologic failure and available phenotypic resistance data, 37 lost
susceptibility to FTC, 29 lost susceptibility to RPV, and 2 lost susceptibility to TDF. Among
these subjects, 37 were resistant to lamivudine, 28 were resistant to etravirine, 26 to
efavirenz, and 12 to nevirapine. Reduced susceptibility was observed to abacavir and/or ddI
in some cases.
2.5.4.8.
Efficacy Against HBV in HIV/HBV Coinfected Subjects
In addition to anti-HIV activity, both FTC and TFV demonstrate potent and selective
inhibition of HBV replication in vitro and in vivo. No activity of RPV was observed against
HBV at concentrations up to 10 PM. Coinfection with HIV-1 increases the risk of HBV
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related progressive disease {6181}, {6180}, {5024}. Antiretroviral medications with dual
activity against both HIV-1 and HBV, such as TDF and FTC, may represent a therapeutic
advantage in terms of controlling the replication of both viruses.
Data supporting the anti-HBV activity of TDF 300 mg once daily in subjects with HIV/HBV
coinfection are available from a variety of sources including a controlled study conducted by
the AIDS Clinical Trials Group (ACTG A5127), retrospective analyses of data from
Gilead-sponsored controlled studies, and published data from uncontrolled studies conducted
by independent investigators.
In ACTG A5127, the mean decrease in serum HBV DNA from baseline was greater in
HIV/HBV coinfected subjects treated with TDF 300 mg than with adefovir dipivoxil 10 mg
{7469}. In substudies of coinfected subjects who participated in the pivotal Phase 3 HIV
clinical trials of TDF (Studies GS-99-907 and GS-99-903), similar significant decreases in
HBV DNA levels were observed in subjects treated with TDF {6586}. Genotyping revealed
that TDF treatment was not associated with the development of the 3TC-resistance YMDD
mutation. Moreover, the anti-HBV efficacy of TDF was unaffected by the presence of the
YMDD mutation. Several external investigator studies provide further support for the
efficacy of TDF in HIV/HBV coinfected subjects {4376}, {6379}, {6837}, {3940}, {4630},
{6849}. Based on this experience, current clinical practice guidelines recommend TDF as the
treatment of choice for patients with HBV and HIV confection who require antiviral therapy,
particularly those with 3TC-resistant infection {6389}.
Tenofovir DF (300 mg once daily) is approved for treatment of HBV monoinfection in the
US, Europe, and other countries. Significant decreases in HBV DNA levels with FTC
200 mg once daily were demonstrated in 2 Phase 2 dose-response studies (FTCB-101 and
FTCB-102) and in 1 Phase 3 study (FTCB-301) of subjects with chronic hepatitis B (without
HIV-1). The efficacy and safety of Truvada is being evaluated in this population.
In pivotal Phase 3 studies of FTC for the treatment of HIV-1 infection, the magnitude of
HBV DNA suppression in HIV/HBV coinfected subjects was similar to that observed in
subjects with HBV monoinfection given FTC 200 mg once daily in FTCB-102.
HBV DNA levels were similarly suppressed for a small number of subjects with
HBV coinfection who received FTC and TDF in Study GS-01-934.
2.5.4.9.
Efficacy Discussion and Conclusions
Emtricitabine, RPV, and TDF are potent and selective HIV-1 reverse transcriptase inhibitors;
each individual agent demonstrates potent and durable efficacy in the treatment of HIV-1
infection in combination with other antiretroviral agents.
In antiretroviral-naive subjects in Study GS-01-934, the antiviral efficacy of the once-daily
regimen of FTC TDF EFV, administered without regard to food, was superior to that of
the CBV (twice daily) EFV (once daily), as demonstrated by the proportion of subjects
who achieved and maintained confirmed HIV-1 RNA 400 copies/mL at Week 48. The
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once-daily regimen of EFV + FTC + TDF demonstrated continued significant and potent
antiretroviral efficacy through 144 weeks of treatment in Study GS-01-934. Genotypic
resistance to EFV (predominantly the K103N mutation) was most commonly observed.
Resistance to FTC (M184V/I mutation) developed infrequently, and no resistance to TDF
(K65R mutation) developed.
Potent and durable efficacy in treatment-naive subjects was similarly demonstrated with the
regimen of TDF + 3TC + EFV in comparison with the regimen of d4T + 3TC + EFV during
144 weeks of treatment in Study GS-99-903. The effectiveness of the TDF regimen was
comparable to that of the d4T regimen for primary and secondary analyses of proportion of
subjects with plasma HIV-1 RNA concentrations 400 copies/mL and 50 copies/mL,
change from baseline in plasma HIV-1 RNA, and change from baseline in CD4 cell count.
The most common resistance mutations in virologic failures were associated with resistance
to EFV (K103N) and 3TC (M184V/I). The K65R mutation occurred in 3% of subjects
treated with TDF during the 144-week double-blind treatment period. In subjects continuing
in the extension phase, efficacy was maintained through 240 weeks of treatment, with no
further reports of K65R development.
Study M02-418 demonstrated potent and durable efficacy in treatment-naive subjects
receiving FTC and TDF with a protease inhibitor (LPV/r once or twice daily). The
effectiveness of regimens was similar for primary and secondary analyses of proportion of
subjects with plasma HIV-1 RNA concentrations 50 copies/mL, change from baseline in
plasma HIV-1 RNA, and change from baseline in CD4 cell count. Resistance to FTC
(M184V/I mutation) developed infrequently, and no resistance to TDF (K65R mutation)
developed.
The efficacy of TMC278 and FTC/RPV/TDF FDC tablets for the treatment of HIV-1
infection in adult patients is based on efficacy data of the Week 48 analysis from 2 Phase 3
registrational trials. The efficacy of TMC278 is further supported by the long-term efficacy
data (up to 192 weeks) from a Phase 2b trial (C204) in HIV-1 infected, treatment-naive adult
subjects (see Module 2.7.3.2.2.2). In the Phase 2 and Phase 3 trials, a total of 779 subjects
have been treated with the recommended dose of TMC278 25 mg once daily. The results
seen in subjects given FTC + RPV + TDF in the 2 studies are similar to those seen in the
2 studies overall since 80% of the subjects received FTC/TDF as their NRTI regimen. Thus,
FTC + RPV + TDF had noninferior efficacy with a higher rate of virologic failure and lower
rates of adverse effects (particularly dizziness, rash, and elevation in total cholesterol)
compared to FTC + EFV + TDF.
In the Week 96 analysis of the Phase 2b dose-finding trial, all TMC278 doses tested were
highly active and demonstrated substantial and durable efficacy across the TMC278 dose
groups.
The efficacy results of the Phase 3 trials demonstrated that in ARV treatment-naive adult
patients, TMC278 dosed at 25 mg once daily with a background regimen consisting of
2 N(t)RTIs demonstrated substantial and sustained efficacy that was noninferior to EFV
600 mg once daily with the same background regimen, a recommended first-line treatment
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for HIV disease. The primary noninferiority endpoint of 48 weeks of treatment in the Phase 3
clinical trials was met and the results of the PP population confirmed the results of the ITT
population. The snapshot analysis confirmed the results of the TLOVR analysis. Different
sensitivity analyses on the pooled Phase 3 data established noninferiority of TMC278 versus
control at the 12% level, demonstrating robustness of the results.
Response rates with TMC278 were high and comparable to control, irrespective of
background regimen and of baseline characteristics such as gender, race, hepatitis coinfection
status, or HIV clade. There was a trend for lower response rates in the TMC278 treatment
group for subjects with high baseline viral loads, which was less evident in the control group.
For both treatment groups, baseline viral load was a statistically significant factor in relation
to time to virologic response, time to treatment failure, and time to virologic failure.
Baseline CD4+ cell count affected virologic response in the TMC278 group, where the
virologic response was higher with higher CD4+ cell count, whereas a minor influence of the
baseline CD4+ cell count on virologic response was observed in the control group.
At Week 48, the TMC278 group showed reconstitution of absolute and relative (%) CD4+
cell count, comparable to that in the control group.
Investigations of potential factors influencing virologic response in the TMC278 group have
identified adherence as the most important predictor of response, followed by exposure to
TMC278, baseline viral load, and CD4+ cell count at baseline. Virologic response analyzed
by adherence measured both by using a patient-completed questionnaire and pill count
showed that greater proportions of virologic responders were seen for subjects who were
adherent than those who were not adherent, and this was observed in both treatment groups.
The number of virologic failures in the Phase 3 trials was limited in both treatment groups,
with comparable proportions of failures with NNRTI RAMs. The proportion of TMC278
virologic failures with emerging N(t)RTI RAMs was approximately double that of the
virologic failures in the control group in the pooled analysis. Among the TMC278 virologic
failures, 50% lost susceptibility to TMC278. TMC278 failures who were resistant to
TMC278 developed phenotypic cross-resistance against EFV and ETR. The control virologic
failures resistant to EFV retained sensitivity to ETR and TMC278 but were cross-resistant to
NVP.
Subjects receiving TMC278 tolerated treatment better and had fewer discontinuations due to
AEs than subjects on control.
The durable antiviral effect of ARV regimens containing TMC278 was also seen in the
results of the long-term Week 192 efficacy analyses of the Phase 2b trial, which
demonstrated a persistent long-term decrease from baseline in viral load and an
immunological benefit. The vast majority of subjects with undetectable viral load
(< 50 copies/mL) at Week 96 maintained this level of virologic suppression to at least
192 weeks of treatment.
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Overall, TMC278 combined with an active background regimen has demonstrated significant
efficacy, which is sustained with long-term follow-up, in a population of HIV-1 infected
ARV treatment-naive adult patients.
With respect to treatment-experienced patients, the clinical data and resistance profiles for
the individual agents provide adequate assurance that the FTC/RPV/TDF FDC tablet will
effectively maintain control of plasma HIV-1 RNA levels. Studies GS-MC-164-0111,
GS-ES-164-0154, GS-US-164-0106, and GS-DE-164-0106 demonstrate the maintenance of
virologic suppression for subjects who switch their NRTIs to FTC/TDF. Efficacy and safety
of FTC, RPV, TDF, and FTC/TDF in treatment-experienced subjects have been
demonstrated in the following studies:
x
Emtricitabine: Study FTC-303 (see Modules 2.7.3.2.1.2.1)
x
Rilpivirine: Trial C202 (see Module 2.7.3.2.2.3.2)
x
Tenofovir DF: Studies GS-98-902 and GS-99-907 (see Module 2.7.3.2.3.2.1)
x
FTC/TDF: GS-MC-164-0111 (SWEET) (see Module 2.7.3.2.5.1)
In conclusion, the potent efficacy and low level of adverse events that has been demonstrated
with the regimens containing FTC + RPV + TDF support the clinical effectiveness of the
FTC/RPV/TDF FDC tablet.
2.5.5.
Overview of Safety
More detailed information on the safety results of individual trials is provided in
Module 2.7.4.
2.5.5.1.
Introduction
The safety profiles of the individual agents in adult HIV-1 infected subjects were primarily
established from pivotal Phase 3 clinical studies in treatment-naive and
treatment-experienced subjects as follows:
x
Emtricitabine: Studies FTC-301A and FTC-303
x
Rilpivirine: Trials C209 and C215 (treatment-naive only)
x
Tenofovir DF: Study GS-99-907
Safety and efficacy for Truvada was primarily established in Studies GS-01-934 and
GS-99-903.
No new supportive clinical efficacy and safety studies for FTC/RPV/TDF FDC tablets were
considered warranted on the basis of available safety data and extensive clinical experience
with the use of FTC and TDF, both alone and in combination, and RPV for the treatment of
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HIV-1 infection in adults. Safety data from Tibotec’s Phase 1 and Phase 2 clinical studies
conducted with RPV are appended to Module 2.7.4 (Appendix 2.7.4.7.3).
The safety profiles of FTC, TDF, and Truvada continue to be monitored through
postmarketing surveillance and are reviewed in PSURs. The cumulative patient exposure for
each product through the last PSUR is presented in Table 20.
Table 20.
Estimated Cumulative Postmarketing Exposure to the Individual
Marketed Products
Period
Cumulative Postmarketing
Exposure (patient-years)
Emtriva (FTC)
Cumulative to 30 June 2010
109,883
Viread (TDF)
1,546,629
Truvada (FTC/TDF)
1,363,365
Product
Given that there is little overlap in the toxicities of FTC, RPV, and TDF, no additional or
exacerbated toxicities would be expected with use of the FTC/RPV/TDF FDC tablet. Clinical
experience is consistent with this conclusion.
The main safety findings from Studies GS-01-934 and GS-99-903 and Trials C209 and C215
are provided in Section 2.5.5.2 and Module 2.7.4. Safety data from Study M02-418 are not
described in this clinical overview since all subjects received a regimen containing FTC and
TDF, and the designated study drugs were LPV/r (see Module 2.7.4).
This safety overview also includes discussion of the clinical trial experience, as well as
several safety topics that require specific consideration for the use of the FTC/RPV/TDF
FDC tablet. Pertinent data, including nonclinical information, clinical trial and postmarketing
experience, are reviewed for the following:
Renal safety (Section 2.5.5.3): due to preclinical findings and case reports of renal events
during postmarketing experience with TDF.
Skin effects (Section 2.5.5.4): due to the occurrence of skin hyperpigmentation in patients
treated with FTC. Certain skin events are side effects commonly observed with drugs of the
NNRTI class and are therefore closely monitored in all clinical trials with TMC278.
Bone toxicity (Section 2.5.5.5): due to preclinical findings and case reports of osteomalacia
associated with proximal tubulopathy during postmarketing experience with TDF.
Mitochondrial toxicity and metabolic effects (Section 2.5.5.6): due to the association of
this toxicity with nucleoside analog therapy.
Neurologic events (Section 2.5.5.7): Certain neurologic events are reported to be associated
with the use of drugs of the NNRTI class and are therefore closely monitored in all trials with
TMC278.
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Psychiatric Events (Section 2.5.5.8): Certain psychiatric events are reported to be associated
with the use of drugs of the NNRTI class and are therefore closely monitored in all TMC278
clinical trials.
Hepatic Events (Section 2.5.5.9): Hepatic AEs were of special interest as in certain cases
ARV treatments have been associated with hepatotoxicity and there is a potential risk of
hepatitis flare in patients with underlying HBV infection following discontinuation of these
agents.
Events related to QT interval prolongation (Section 2.5.5.10): In a thorough QT (TQT)
trial, a QT interval prolongation effect of TMC278 was observed in healthy volunteers at
doses that are multiples (3 to 12 times higher) of the 25 mg once daily dose selected for
further development.
Endocrine events (Section 2.5.5.11): Endocrine monitoring, including gonadal, adrenal and
thyroid, was included as a way of assessing adrenal and thyroid function, because effects on
the adrenal gland were observed in rats, dogs and cynomolgus monkeys with TMC278
Special populations (Section 2.5.5.12): patients coinfected with HIV-1 and HBV or
hepatitis C virus (HCV), pregnancy, elderly patients, pediatric patients, and patients with
renal or hepatic impairment are specifically considered.
2.5.5.2.
Summary of Clinical Trial Safety Experience
2.5.5.2.1.
Safety in Study GS-01-934
The once-daily regimen of EFV + FTC + TDF was well tolerated through 144 weeks of
treatment in Study GS-01-934, and demonstrated a preferential safety profile compared with
the EFV + Combivir regimen.
Through Week 144, at least 1 treatment-emergent AE was reported for 95% of subjects
(245/257) in the FTC + TDF group and 97% of subjects (246/254) in the Combivir group
(Table 21). The most frequently reported treatment-emergent AEs (for at least 20% of either
treatment group) were diarrhea (28%, 73/257), dizziness (28%, 71/257) nausea (26%,
66/257), and headache (20%, 51/257) in the FTC + TDF group and nausea (33%, 83/254),
dizziness (29%, 74/254), and diarrhea (20%, 50/254) in the Combivir group.
Five deaths (2 in the FTC + TDF group and 3 in the Combivir group) were reported through
Week 144, all of which were considered unrelated to treatment. Treatment-emergent serious
adverse events (SAEs) were reported for 11% of subjects (29/257) in the FTC + TDF group
and 14% of subjects (35/254) in the Combivir group. AEs leading to study drug
discontinuation occurred in a significantly smaller percentage of subjects in the FTC + TDF
group compared with the Combivir group (5% [13 subjects] vs 11% [29 subjects], p = 0.010).
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Table 21.
Final
GS-01-934: Treatment-Emergent Adverse Events Reported in at
Least 10% of Subjects in Either Treatment Group (Safety
Analysis Set)
EFV + FTC + TDF
(N 257)
AEs by System Organ Class and Preferred Terma
EFV + Combivir
(N 254)
n
%
n
%
245
95%
246
97%
Diarrhoea
73
28%
50
20%
Nausea
66
26%
83
33%
Vomiting
20
8%
33
13%
46
18%
46
18%
Nasopharyngitis
45
18%
33
13%
Upper Respiratory Tract Infection
48
19%
27
11%
Sinusitis
33
13%
17
7%
26
10%
20
8%
Headache
51
20%
43
17%
Dizziness
71
28%
74
29%
Depression
38
15%
33
13%
Insomnia
44
17%
45
18%
Abnormal Dreams
45
18%
34
13%
Cough
31
12%
31
12%
Pharyngolaryngeal Pain
14
5%
28
11%
39
15%
33
13%
Any AE
Gastrointestinal Disorders
General Disorders and Administrative Site Conditions
Fatigue
Infections and Infestations
Musculoskeletal and Connective Tissue Disorders
Back Pain
Nervous System Disorders
Psychiatric Disorders
Respiratory, Thoracic, and Mediastinal Disorders
Skin and Subcutaneous Tissue Disorders
Rash
All adverse events reported in t 10% of subjects in either treatment group are included, regardless of severity grade or
relationship to treatment. Each subject is counted only once per treatment and preferred term.
Source: Module 5.3.5.1, GS-01-934, 144-week CSR, Section 11.1, Table 33
a
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No changes in the safety profile of EFV, FTC or TDF were observed with 48 weeks of
coadministration compared to previous experience with the use of the individual agents in
other combination regimens. Through Week 144 in Study GS-01-934, treatment-emergent
AEs considered by the investigator as possibly or probably related to the complete study
regimen (EFV + FTC + TDF or CBV + EFV) were reported for 69% of subjects (177/257) in
the FTC + TDF group and 76% of subjects (193/254) in the Combivir group. The most
frequently reported treatment-emergent AEs (for at least 10% of either treatment group)
related to study regimen were dizziness (25%, 63/257), nausea (18%, 46/257), and abnormal
dreams (17%, 44/257) in the FTC + TDF group and nausea (27%, 69/254), dizziness (26%,
66/254), abnormal dreams (13%, 34/254), and fatigue (10%, 25/254) in the Combivir group.
There was no evidence of a TDF effect on renal function as determined by the evaluation of
serum creatinine and serum phosphorus concentrations and the lack of occurrence of
clinically significant renal-related AEs (see Section 2.5.5.3). Similarly, there was no evidence
of bone toxicity associated with TDF, as indicated by the similar incidence of bone fractures
between the treatment groups; all fractures were considered by the investigator as not related
to any of the study drugs, and no change in study regimen dosing was made as a result of any
fracture. Few subjects reported skin hyperpigmentation: 15 subjects in the
EFV + FTC + TDF group and 9 subjects in the CBV + EFV group. Hyperpigmentation was
Grade 2 in severity for 2 subjects (one in each treatment group) and Grade 1 for all other
subjects.
Treatment effects on lipid metabolism favored the EFV + FTC + TDF regimen (see
Section 2.5.5.6 and Module 2.7.4.3.4).
In summary, the once-daily regimen of FTC + TDF + EFV has demonstrated an acceptable
safety profile in treatment-naive HIV-1 infected subjects through long-term treatment. The
FTC + TDF + EFV regimen was better tolerated than the CBV + EFV regimen, as evidenced
by the significantly lower rate of study drug discontinuation due to an AE. There was no
effect on renal function or evidence of bone toxicity, and few reports of hyperpigmentation.
2.5.5.2.2.
Safety in Study GS-99-903
The once-daily regimen of TDF + 3TC + EFV was well tolerated through 144 weeks of
treatment in Study GS-99-903, and demonstrated a preferential safety profile compared with
the d4T + 3TC + EFV regimen.
Through 144 weeks of double-blind treatment, the most common AEs in both treatment
groups were headache, viral infection and diarrhea, each of which occurred with similar
incidences between treatment groups. Most AEs were of mild or moderate severity. Only
10 subjects (3%) in the TDF + 3TC + EFV group compared with 21 subjects (7%) in the
d4T + 3TC + EFV group had Grade 3/4 AEs that were considered to be possibly or probably
related to study treatment (i.e., TDF or d4T).
Eleven deaths (5 in the TDF + 3TC + EFV group and 6 in the d4T + 3TC + EFV group)
occurred during the 144-week study period and were due to largely complications of
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advanced HIV disease; none were considered by the investigator to be related to study
medication. The incidence of SAEs was similar between the 2 treatment groups. SAEs were
generally of a type that would be expected in a study population of HIV-1 infected subjects
requiring antiretroviral therapy. Few SAEs were considered possibly or probably related to
study treatment. There was a higher incidence of discontinuations due to AEs in the
d4T + 3TC + EFV group (13%) compared with the TDF + 3TC + EFV group (6%), mainly
attributed to the higher rate of occurrence of lipodystrophy with the d4T regimen. During the
study, 47 subjects substituted nevirapine for EFV (7% of subjects in the TDF group and 9%
of subjects in the d4T group). The most common reason for substitution was EFV-associated
central nervous system toxicity (6% in each group; other reasons included rash, pregnancy,
and protocol exception).
The incidences of serum creatinine elevations and hypophosphatemia were similar between
the 2 treatment groups and there were no clinically significant drug-related renal AEs (see
also Section 2.5.5.3). There was no increased risk of bone fractures or evidence for clinically
relevant bone abnormalities with the TDF regimen over the 144-week treatment period (see
also Section 2.5.5.5).
The results of the assessment of metabolic effects and potential mitochondrial toxicities
through 144 weeks indicated a more favorable safety profile with the TDF regimen compared
with the d4T regimen as demonstrated by the overall incidence of events related to potential
mitochondrial toxicity, changes in body weight and limb fat, and changes in serum lipid
profiles (see Section 2.5.5.6 and Module 2.7.4.4.5.1) {7013}. The incidence of Grade 3 and
Grade 4 laboratory abnormalities was similar in both treatment groups, except for serum
cholesterol and triglyceride elevations that were more common in the d4T + 3TC + EFV
group (15% and 14%, respectively) compared with the TDF + 3TC + EFV group (5% and
3%, respectively).
During the open-label extension phase, TDF was well tolerated both in the subset of subjects
who continued TDF (mean of 248 weeks of TDF treatment) and those who switched from
d4T to TDF (mean of 99 weeks of TDF treatment). Most AEs were mild to moderate in
severity and did not result in treatment discontinuation. Only 1 subject discontinued TDF
treatment due to an AE (asymptomatic serum amylase and lipase increased). There was no
evidence of any clinically significant toxicity related to the use of TDF. The renal safety
profile remained stable in the TDF/TDF group through the extended treatment period. The
small changes in bone mineral density (BMD) that were seen in the first 48 weeks of
double-blind treatment were nonprogressive for the remainder of TDF treatment. In subjects
who switched from d4T to TDF in the open-label phase, there was a significant improvement
in the lipid profile and a marked increase in limb fat.
In summary, during long-term treatment in Study GS-99-903, TDF administered in
combination with 3TC and EFV was well tolerated in antiretroviral-naive HIV-1 infected
subjects. The results of several key measures used to assess safety and tolerability, including
discontinuations due to AEs and the serum lipid profile, indicate that the TDF regimen has a
more favorable safety profile than the d4T regimen.
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2.5.5.2.3.
Safety in Trials C209 and C215
2.5.5.2.3.1.
Analysis of Safety Data and Extent of Exposure
Final
The integrated overview of the safety and tolerability profile of the recommended dose
TMC278 25 mg once daily in HIV-1 infected subjects is based on the primary 48-week
safety analysis of the pooled Phase 3 trials. In the Phase 3 trials, 686 subjects started
treatment with TMC278 25 mg once daily (taken with a meal), while the pooled control
group consisted of 682 subjects receiving EFV (taken without food). Subjects received
TMC278 or EFV plus a background regimen containing 2 investigator-selected N(t)RTIs: in
C209, the fixed background regimen was FTC/TDF, and in C215, the background regimen
was either ABC/3TC, AZT/3TC, or FTC/TDF
The median treatment duration was approximately 55 weeks in both treatment groups. A total
of 611 subjects (89.1%) were exposed to TMC278 for at least 48 weeks.
The double-blind, double-dummy controlled design and the similarity of the background
regimen in the Phase 3 trials allows for a relevant safety assessment and ensured a
comparative evaluation of safety between TMC278 and EFV as control.
Further details on safety in the Phase 3 trials are provided in the TMC278-C209 CRR and the
TMC278-C215 CRR (Module 5.3.5.1).
2.5.5.2.3.2.
Overall Safety Profile of TMC278 in Pooled Phase 3 Trials
2.5.5.2.3.2.1.
Overall Incidence of AEs in Pooled Phase 3 Trials of TMC278
(C209 and C215)
This section provides an overall summary of AEs in the Phase 3 pooled analysis.
An overview of AEs, including AEs of special interest, reported in the Phase 3 trials is
provided in Table 22.
The incidence of any AE was similar in both treatment groups (89.8% in the TMC278 group
and 92.2% in the control group).
Most AEs were Grade 1 or 2 in severity. Grade 3 or 4 AEs were reported by 13.3% of
subjects in the TMC278 group and by 18.0% of subjects in the control group.
A lower proportion of subjects in the TMC278 group (46.4%) than in the control group
(64.1%) had at least 1 AE that was assessed by the investigator to be treatment-related.
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The proportion of subjects experiencing AEs leading to permanent discontinuation was
smaller in the TMC278 group (3.4%) than in the control group (7.6%). The most common
AEs leading to permanent discontinuation on TMC278 belonged to the system organ class
(SOC) psychiatric disorders (1.5% versus 2.2% on control). In the control group, subjects
mostly discontinued due to AEs in the SOCs of skin and subcutaneous tissue disorders
(0.3% on TMC278 versus 1.8% on control), mostly driven by the individual preferred term
rash, infections and infestations (0.3% on TMC278 versus 1.3% on control), and psychiatric
disorders (1.5% on TMC278 versus 2.2% on control).
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Table 22.
Final
Rilpivirine Studies C209 and C215: Summary of Adverse Events
(Phase 3 Week 48 Analysis)
TMC278
N = 686
Control
N = 682
55.7
(0 - 87)
55.6
(0 - 88)
740.1
714.4
616 (89.8)
629 (92.2)
607 (88.5)
618 (90.6)
Grade 1
561 (81.8)
565 (82.8)
Grade 2
333 (48.5)
366 (53.7)
91 (13.3)
123 (18.0)
79 (11.5)
114 (16.7)
AE Summary, n (%)
Treatment duration (weeks)
Median (range)
Subject-years of exposurea
Any AE
a
Any Grade 1 or 2 AE
Any Grade 3 or 4 AE
Grade 3
Grade 4
23 (3.4)
23 (3.4)
b
318 (46.4)
437 (64.1)
b
109 (15.9)
212 (31.1)
1 (0.1)
4 (0.6)
Any SAE
45 (6.6)
55 (8.1)
AE leading to discontinuation
23 (3.4)
52 (7.6)
AE leading to temporary
discontinuation
28 (4.1)
44 (6.5)
Any skin event of interestd,e
96 (14.0)
177 (26.0)
Rash (grouped term)
51 (7.4)
150 (22.0)
276 (40.2)
388 (56.9)
Any neurologic event of interest
184 (26.8)
308 (45.2)
Any psychiatric event
164 (23.9)
198 (29.0)
Any hepatic event of interest
38 (5.5)
45 (6.6)
Any event of interest potentially
related to QT interval prolongationd,g
3 (0.4)
8 (1.2)
Any endocrine event of interestd,g
34 (5.0)
26 (3.8)
Any treatment-related AE
Any treatment-related AE and at
least Grade 2
Death
c
Any neuropsychiatric event of
interestd,f
d,g
N = number of subjects per treatment group; n = number of observations.
a
Post hoc analyses were performed to determine the number of subjects with Grade 1 or 2 AEs.
b Defined as possibly, probably, or very likely related to treatment in the opinion of the investigator.
c
Includes SAEs with an outcome of death.
d AEs of interest were not identified from single relevant SOCs, but were based on selected AE preferred terms from a
number of relevant SOCs.
e
Presented overall for event of interest category (defined in Appendix 2.7.4.7.3, Section 1.3.2.4.1) and by grouped term.
f
Presented overall for neuropsychiatric events of interest and by neurologic/psychiatric event of interest categories
g
Presented overall for event of interest category
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The most commonly reported AEs in the TMC278 group (in at least 10.0% of subjects) were
headache (13.8%), nausea (13.4%), diarrhea (11.4%) and nasopharyngitis (10.1%). These
events were reported at a similar incidence in the control group. The most clear differences in
common AEs between treatment groups were in favor of TMC278 and were seen for rash
(individual preferred term) (5.2% with TMC278 versus 13.2% with control) and dizziness
(9.9% with TMC278 % versus 28.4% with control) (see Module 2.7.4.2.1.1.2, Table 25).
When considering treatment-related AEs, dizziness (TMC278: 8.0%; control: 26.2%),
somnolence (TMC278: 3.6%; control: 7.2%), rash (individual preferred term) (TMC278:
2.5%; control: 8.9%), disturbance in attention (TMC278: 0.7%; control: 2.5%), and vertigo
(TMC278: 0.3%; control: 2.3%) were reported by lower proportions of subjects on TMC278
than on control.
Statistical comparisons for the Phase 3 pooled analysis were performed as predefined in the
statistical analysis plan, using the TMC278/control odds ratio (with associated 95% CIs) and
Fisher exact test for the parameters shown in Figure 6 and Figure 7. For any single preferred
terms (or the planned psychiatric event of interest grouped term, “abnormal
dreams/nightmare”) comparisons were made when the incidence was more than 10% overall,
regardless of relationship to study medication.
Statistical testing comparing the TMC278 and control groups in the incidence of AEs
reported in more than 10% of subjects (by preferred term, using the Fisher exact test),
revealed statistically significant differences in favor of TMC278 for dizziness (p < 0.0001),
abnormal dreams/nightmare (p = 0.0093) and for the individual preferred term of rash
(p < 0.0001). No statistically significant differences were found in favor of control for the
AEs tested.
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Figure 6.
Final
Medication - Grouped terms (Phase 3 Week 48 Pooled Analysis)
P-values from Fisher exact test
EOI, event of interest
Source: Module 5.3.5.3, TMC278-C904-Anal-Saf-AE, Display SAF.19
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Figure 7.
Final
Medication – Most Frequent (> 10% overall) Individual Preferred
Terms (Phase 3 Week 48 Pooled Analysis)
P-values from Fisher exact test
Source: Module 5.3.5.3, TMC278-C904-Anal-Saf-AE, Display SAF.19
For details, refer to Section 2.5.5.4.2 on rash, Section 2.5.5.7.2 on neurologic events of
interest and Section 2.5.5.8.2 on psychiatric event of interest.
2.5.5.2.3.2.2.
Mortality in Pooled Phase 3 Trials of TMC278
In the 35 RPV clinical trials with safety data included in this submission, a total of 9 subjects
died; 4 subjects in the Phase 2b trial (see Module 2.7.4, Appendix 2.7.4.7.3), and 5 subjects
in the Phase 3 trials. None of these deaths was considered related to study medication.
In the 2 Phase 3 trials, 5 subjects had died at the time of the primary Week 48 analysis.
One subject (0.1%) in the TMC278 group due to bronchopneumonia and 4 subjects (0.6%) in
the control group due to Burkitt’s Lymphoma, cerebral toxoplasmosis and respirator failure
(in 1 subject), dysentery, and cerebrovascular accident.
Further details on AEs leading to death in the Phase 3 trials are provided in
Module 2.7.4.2.1.2.2. Details on AEs leading to death in the Phase 2b trial (C204) are
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provided in Module 2.7.4, Appendix 2.7.4.7.3, Section 4.3.1.3 (Week 96 analysis) and
Module 2.7.4, Appendix 2.7.4.7.3, Section 4.4.1.3 (Week 192 analysis).
2.5.5.2.3.2.3.
SAEs and Other Significant AEs in Pooled Phase 3 Trials of TMC278
SAEs were reported during the treatment period in the 2 Phase 3 trials at similar rates in the
2 treatment groups, by 45 subjects (6.6%) in the TMC278 group and 55 subjects (8.1%) in
the control group.
The reported SAEs were from a variety of SOCs, and many occur commonly in HIV-infected
patients. For each treatment group, the highest incidence of SAEs was observed in the SOC
of infections and infestations (2.6% in the TMC278 group and 2.5% in the control group).
The only notable difference in incidence of SAEs between TMC278 and control was seen in
the SOC of hepatobiliary disorders (0.9% on TMC278 versus 0.1% on control).
The incidence of treatment-related SAEs was 1.0% (7 subjects) in the TMC278 group and
0.9% (6 subjects) in the control group. The only SOCs in which more than 1 subject had a
treatment-related SAE was the SOC of psychiatric disorders (3 subjects [0.4%] on TMC278
versus 2 subjects [0.3%] on control) and the SOC of investigations (1 subject [0.1%] on
TMC278 versus 2 subjects [0.3%] on control).
In the control group, more subjects discontinued due to AEs and generally did so earlier than
subjects in the TMC278 group, and the difference was sustained throughout the treatment
period. The proportion of subjects who experienced an AE leading to permanent
discontinuation was 3.4% in the TMC278 group and 7.6% in the control group. The
difference between the TMC278 and control groups was mainly driven by the SOC of skin
and subcutaneous tissue disorders (0.3% versus 1.8%), infections and infestations
(0.3% versus 1.3%) and psychiatric disorders (1.5% versus 2.2%).
2.5.5.2.3.2.4.
Clinical Laboratory Evaluations in Pooled Phase 3 Trials of TMC278
In the TMC278 group, changes over time in the selected laboratory parameters, if any, were
generally modest in either treatment group of the pooled Phase 3 trials and considered not
clinically relevant.
TMC278 was not found to have any clinically relevant effect on hepatic parameters,
pancreatic parameters amylase and lipase, glucose and insulin or lipids. In general, changes
over time for these parameters were not substantially different between the 2 treatment
groups.
Initial decreases in hemoglobin, mainly observed in the AZT/3TC subgroup, were consistent
with the known effect of AZT.
Small mean increases from baseline for creatinine were observed in the TMC278 group,
accompanied by decreases in estimated glomerular filtration rate for creatinine as calculated
by modification of diet in renal disease (MDRD) formula (eGFRcreat) below baseline levels,
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but the likely effect of TMC278 on tubular secretion of creatinine is not considered of
clinical relevance.
In addition, there has been no trend or signal of adrenal dysfunction. Thyroid monitoring was
not done in Phase 3 trials as close monitoring of thyroid hormone levels in the Phase 2b trial
did not identify any clinically relevant effects of TMC278 on thyroid function.
The most frequently reported treatment-emergent graded laboratory abnormalities in any
treatment group were elevated total and LDL cholesterol levels, which were reported at a
lower frequency in the TMC278 group compared to the control group.
Clinical laboratory evaluations over time are presented by background N(t)RTI subgroup for
parameters that are known to be affected by background N(t)RTI regimen. Since the number
of subjects in the ABC/3TC subgroup was small (5.0% of subjects overall), data for this
subgroup are not discussed as comparisons with this subgroup are not considered
meaningful.
The incidence of treatment-emergent Grade 3 or 4 laboratory abnormalities was lower in the
TMC278 group (10.9%) than in the control group (17.6%).
The most common Grade 3 and 4 laboratory abnormalities in the TMC278 group were
increased pancreatic amylase (2.9% in the TMC278 group and 4.0% in the control group),
increased aspartate aminotransferase (AST) (2.0% in the TMC278 group and 2.8% in the
control group), and increased alanine aminotransferase (ALT) (1.5% in the TMC278 group
and 3.4% in the control group). No Grade 4 laboratory abnormalities were reported in more
than 2 subjects (0.3%) in the TMC278 group, with the exception of ALT (5 subjects, 0.7%)
and AST (3 subjects, 0.4%), and Grade 4 laboratory abnormalities were reported in no more
than 1.3% of subjects in the control group.
Further details on laboratory safety in Phase 3 trials are provided in Module 2.7.4.3.1.2.
Hemoglobin
In the overall pooled Phase 3 TMC278 population, mean hemoglobin values remained close
to baseline levels early on in the trial and showed a similar pattern in both treatment groups.
At Week 48, mean hemoglobin values increases above baseline to values of 5.3 g/L on
TMC278 and 4.9 g/L on control.
In the Phase 2b trial C204, decreases in hemoglobin levels (and events of anemia) occurred
predominantly in the subgroup of patients using AZT/3TC as the N(t)RTI backbone (see
Module 2.7.4, Appendix 2.7.4.7.3, Section 4.3.2.2). Review of the mean changes in
hemoglobin over time by background regimen in the pooled Phase 3 analysis indicates that
initial hemoglobin decreases only occurred in the AZT/3TC subgroup (Figure 8), consistent
with the known hematotoxic effects of AZT {2226}.
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Figure 8.
Final
Rilpivirine Studies C209 and C215: Mean Change (r95% CI)
from Baseline in Hemoglobin by Background Regimen: FTC/TDF
(Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48
Pooled Analysis)
FTC/TDF
AZT/3TC
ABC/3TC
Source: Module 2.7.4.3.6.1.1, Figure 20
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In the AZT/3TC subgroup, maximum mean decreases from baseline were seen at Week 8,
after which hemoglobin gradually returned to baseline levels by Week 48. No notable mean
decreases in hemoglobin were seen in the TMC278 group for the other background regimen
subgroups.
Hepatic Parameters
The laboratory evaluation of hepatic parameters in the TMC278 group showed mean
decreases from baseline for AST and ALT that stabilized over time. These changes were not
different from the control group and considered not clinically relevant.
Most individual AST and ALT abnormalities in TMC278 treated subjects were Grade 1 or 2
(i.e., mild or moderate) in severity; their incidence was not higher than in the control group.
Incidences of Grade 3 and 4 ALT and AST abnormalities were 2.0% in the TMC278 group
and 2.8% in the control group for increased AST and 1.5% in the TMC278 group and 3.4%
in the control group for increased ALT.
Grade 2 or 3 hyperbilirubinemia was reported at a higher incidence in the TMC278 group
(3.1%) than in the control group (0.4%).
Pancreatic Parameters
Small mean increases from baseline in pancreatic amylase and lipase were initially observed
in the TMC278 group followed by small mean decreases from baseline. A similar pattern
was seen in the control group and the changes in pancreatic amylase and lipase in both
treatment groups were considered not clinically relevant.
Renal Parameters
Serum creatinine changes over time were observed in the Phase 2b trial of TMC278. Based
on investigations in trial C131, there appeared to be no effect on estimated glomerular
filtration rate for cystatin C (eGFRcyst), suggesting that creatinine changes appeared to be
related to NNRTI effects on the disposition of creatinine rather than to renal toxicity. There is
also a known potential tubulotoxicity with TDF, and an effect of decreasing eGFR. For these
reasons, creatinine and eGFRcreat changes were analyzed in the Phase 3 trials and blood
cystatin C (eGFRcyst) was analyzed in trial C215, overall and by background regimen.
In the overall pooled Phase 3 TMC278 population, small mean increases in serum creatinine
were observed for the TMC278-treated subjects, from the first on-treatment assessment
onwards and remained stable over the treatment period, ranging from 0.06 mg/dL at the
first on-treatment assessment to 0.09 mg/dL at Week 48. For control-treated subjects, serum
creatinine fluctuated around the baseline level over the treatment period.
The mean change from baseline in serum creatinine over time in the pooled Phase 3 analysis
is presented for the subgroups of subjects receiving FTC/TDF, AZT/3TC and ABC/3TC in
Figure 9. Mean serum creatinine increases were observed for TMC278-treated subjects in
each background regimen subgroup, but these were greater in the FTC/TDF subgroups
compared to the AZT/3TC subgroup. In the control group, mean decreases in serum
creatinine from baseline were observed for the AZT/3TC subgroup consistently from Week 2
up to Week 48, whereas no notable difference from baseline was observed for subjects in the
control group treated with FTC/TDF.
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Figure 9.
Final
from Baseline in Creatinine by Background Regimen: FTC/TDF
(Top); AZT/3TC (Middle); ABC/3TC (Bottom) (Phase 3 Week 48
Pooled Analysis of C209 and C215)
FTC/TDF
AZT/3TC
ABC/3TC
Source: Module 2.7.4.3.3.1, Figure 8
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Consistent with observations of creatinine increases, a decrease in eGFRcreat was observed,
which remained stable over the 48 weeks with values of 7 to 10 mL/min/1.73m2 from
Week 2 to Week 48. The mean decreases observed for TMC278-treated subjects were greater
in the FTC/TDF subgroup than in the AZT/3TC subgroup. A decrease in eGFRcreat is a
known effect of TDF.
Conversely, in the control group, mean eGFRcreat did not change significantly from baseline
during treatment.
The mean decreases observed for TMC278-treated subjects were greater in the FTC/TDF
subgroup than in the AZT/3TC subgroup.
In the control group, mean increases from baseline were observed in eGFRcreat throughout the
trial for each of the background regimen subgroups but this was least pronounced for the
FTC/TDF subgroup. A decrease in eGFRcreat is a known effect of TDF.
There were no treatment discontinuations due to renal impairment or elevated serum
creatinine.
Exploratory analyses performed in the Phase 1 trial C131 (refer to Module 2.7.4,
Appendix 2.7.4.7.3, Section 6.1.4.1.1) to investigate the effects of TMC278 on the markers
of renal function, i.e., markers of glomerular filtration and proximal tubular function,
demonstrated that TMC278 does not affect the eGFRcyst, nor does it affect proximal tubular
function {11576}. In order to further evaluate whether the effect of TMC278 on serum
creatinine reflected a true change in GFR or could have an alternative explanation, such as an
interaction with the tubular secretion of creatinine, cystatin C was measured in subjects in the
C215 trial at baseline, Week 2 and Week 24. One of the reasons why cystatin C is accepted
to be a better marker of glomerular filtration rate (GFR) than creatinine is because it is freely
filtered by the glomeruli without proximal tubular secretion {15884}, {15851}. The results of
this analysis show a small mean increase in eGFRcyst in the TMC278 group at Week 2
(+2.6 mL/min with TMC278 and 5.3 mL/min with control) and at Week 24 (+21.7 mL/min
with TMC278 and +31.4 mL/min with control). The increase in eGFRcyst was seen in all
subgroups by background regimen, at Week 2 and at Week 24, with TMC278 and with
control. These data indicate that there is no TMC278-induced nephrotoxicity.
The results of the analysis of cystatin C performed in trial C215 are described in an
addendum to the CRR (Module 5.3.5.1, TMC278-C215-W48-CRR-Add).
Lipids
Mean changes from baseline in total cholesterol, high density lipoprotein (HDL) cholesterol,
total cholesterol/HDL cholesterol ratio, low density lipoprotein (LDL) cholesterol and
triglycerides are presented graphically in Figure 10. Fasted values are presented for all lipid
parameters.
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Figure 10.
Final
from Baseline in Total Cholesterol, HDL Cholesterol, Total
Cholesterol/HDL Cholesterol Ratio, LDL Cholesterol and
Triglycerides Over Time (Fasted) (Phase 3 Week 48 Pooled
Analysis)
Total Cholesterol
HDL Cholesterol
Total Cholesterol/HDL Cholesterol Ratio
LDL Cholesterol
Triglycerides
Source: Module 2.7.4.3.4.1, Figures 13–17
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Changes over time in laboratory lipid parameters were less pronounced in the TMC278
group than in the control group, with statistically significant differences between the
2 treatment groups for total, HDL, LDL cholesterol, and triglycerides (all p < 0.001).
Mean total and LDL cholesterol values over time remained close to baseline in the TMC278
group, while mean values for these lipids increased significantly in the control group
(p < 0.001). The increase in HDL cholesterol over time was less pronounced with TMC278
than with control subjects, and there was no difference between treatment groups at Week 48
in decrease from baseline of the total cholesterol/HDL ratio. Mean triglyceride values
remained close to baseline throughout the trial in both treatment groups, showing a small
decrease with TMC278 and a small increase with control.
The most frequently reported treatment-emergent graded laboratory abnormalities in any
treatment group were elevated LDL cholesterol levels, in the 2 treatment groups, reported at
a higher frequency in the control group compared to the TMC278 group. Grade 2 or 3
abnormalities in total cholesterol were reported in a total of 5.0% of subjects in the TMC278
group compared to 18.4% in the control group, and Grade 2 to 3 abnormalities in LDL
cholesterol were reported in a total of 5.5% of subjects in the TMC278 group compared to
15.3% in the control group. Four subjects had Grade 4 abnormalities in triglycerides; all were
in the control group. The use of lipid lowering drugs was low in this patient population
(2.2% and 4.0% of subjects in the TMC278 and control groups, respectively).
Grade 3 or 4 laboratory abnormalities in lipids were more common on control than on
TMC278. The differences between the treatment groups in the incidence of Grade 3 or
4 increases were statistically significant in favor of TMC278 for total cholesterol, LDL
cholesterol and triglycerides (p 0.001) (post hoc analyses).
Lipid data in support of the FTC/RPV/TDF Tablet
Changes from baseline in total cholesterol, LDL cholesterol, HDL cholesterol, and
triglycerides in subjects receiving RPV plus FTC/TDF in Studies C209 and C215 are
presented in Table 23. The mean changes from baseline were smaller in the RPV + FTC/TDF
arm versus the EFV + FTC/TDF arm (see Module 2.7.4.3.4.1).
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Table 23.
Final
Rilpivirine Studies C209 and C215: Lipid Values Reported in
Subjects Receiving RPV or EFV in Combination with FTC/TDF
RPV + FTC/TDF
N = 550
Baseline
EFV + FTC/TDF
N = 546
Week 48
Baseline
Week 48
Mean (mg/dL)
Mean Changea
(mg/dL)
a
Mean (mg/dL)
Mean Change
(mg/dL)
Total cholesterol (fasted)
162
-0.4
161
26
HDL cholesterol (fasted)
41
3
40
10
LDL cholesterol (fasted)
97
-2
96
13
Triglycerides (fasted)
124
-12
132
12
a
The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and
Week 48 values.
Source: Module 2.7.4.3.4.1, Table 93
Glucose, Insulin, and Homeostasis Model Assessment Insulin Resistance
No clinically relevant changes in mean fasted serum glucose or insulin levels were noted
throughout the treatment period in the TMC278 group and the control group. Minor changes
in Homeostasis Model Assessment Insulin Resistance (HOMA-IR) in the TMC278 group
and the control group were also not considered clinically relevant.
2.5.5.2.3.2.5.
Electrocardiogram (ECG) and Vital Signs in Pooled Phase 3 Trials of
TMC278
No effect of TMC278 on vital sign parameters was seen. There were no consistent or
clinically relevant changes over time in vital signs and there were also no clinically relevant
differences in the incidence of treatment-emergent vital sign abnormalities between the
treatment groups. Vital signs abnormalities reported as AEs were reported at low incidence in
both treatment groups.
QTc interval results for the Phase 3 pooled analysis are discussed in Section 2.5.5.10,
together with the analysis of potential events of interest for QT interval prolongation.
For other ECG parameters (Heart Rate, PR interval and QRS interval), small fluctuations
were observed over the 48-week treatment period and there were no consistent or clinically
relevant changes over time in these parameters.
There were also no clinically relevant differences between the TMC278 and control groups
in the incidence of treatment-emergent ECG abnormalities. The incidence of ECG
abnormalities reported as AEs was low and similar in both treatment groups. The most
commonly reported ECG-related AEs were bundle branch block right (1.3% subjects with
TMC278 group and 1.5% with control group), and palpitations (1.7% with TMC278 group
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Final
and 1.0% with control). There was no difference between the TMC278 group and the control
group with respect to the incidence of treatment-emergent ECG abnormalities in any of the
background N(t)RTI regimen subgroups.
2.5.5.2.3.2.6.
Adrenal Safety in Pooled Phase 3 Trials of TMC278
To determine whether there was an effect of TMC278 or control on the biosynthesis of
adrenal and gonadal hormones in humans, basal cortisol, 17-OH progesterone, aldosterone,
androstenedione, dehydroepiandrosterone sulphate (DHEAS), progesterone and testosterone
were assessed at specified time points, before and during double-blind treatment in the Phase
3 trials. Adrenocorticotropic hormone (ACTH) stimulation tests were routinely done at
baseline and at Week 48, and additionally, based on basal cortisol results or an abnormal
ACTH test.
There were no clinically relevant changes in basal cortisol, 17-OH progesterone, or
aldosterone over time and no consistent or clinically relevant changes for the other endocrine
parameters (androstenedione, DHEAS, luteinizing hormone [LH], and testosterone) in either
treatment group.
The mean increase from baseline at Week 48 for maximum change in cortisol after ACTH
stimulation observed in the TMC278 group (16.5 nmol/L) was lower than the increase
observed in the control group (58.1 nmol/L). Neither treatment affected the mean increases
from baseline for maximum change in 17-OH progesterone and aldosterone after ACTH
stimulation at Week 48.
The incidence of abnormal cortisol responses after ACTH stimulation is presented in
Table 24.
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Table 24.
Final
Rilpivirine Studies C209 and C215: Treatment-Emergent
Abnormal Cortisol Response to ACTH Stimulation (Worst Case)
(Phase 3 Week 48 Pooled Analysis)
Parameter
Abnormality, n (%)
TMC278
N = 686
Control
N = 682
593
558
Any abnormal ACTH test
23 (3.9)
8 (1.4)
450, 500 nmol/L
13 (2.2)
4 (0.7)
< 450 nmol/L
10 (1.7)
4 (0.7)
ACTH stimulation test at Week 48
N'
ACTH stimulation tests in the course of the 48-week treatment period, including Week 48
N'
643
605
Any abnormal ACTH test
38 (5.9)
13 (2.1)
450, 500 nmol/L
18 (2.8)
7 (1.2)
< 450 nmol/L
20 (3.1)
6 (1.0)
At least 2 consecutive abnormal
ACTH test
11 (1.7)
0
N = overall number of subjects, N' = number of subjects per test and treatment group; n = number of observations.
A test result was defined as abnormal when none of the cortisol values at T0, T30, or T60 was t 500 nmol/L.
Percentages are calculated relative to the number of subjects with data.
Source: Module 2.7.4.4.3.2, Table 116
The incidence of a treatment-emergent abnormal cortisol response to ACTH stimulation at
Week 48 was slightly higher in the TMC278 group than in the control group, both at
Week 48 (3.9% with TMC278 compared to 1.4% with control) as during the entire treatment
period (5.9% with TMC278 versus 2.1% with control). The incidence of at least
2 consecutive abnormal cortisol responses (< 500 nmol/L) to ACTH stimulation was 1.7% in
the TMC278 group compared to none in the control group.
No subjects discontinued the trial due to an AE of blood cortisol decreased (nor for any other
endocrine event of interest). There were no clinical signs or symptoms of adrenal
insufficiency in either treatment group.
All data related to adrenal safety from preclinical and clinical trials were thoroughly assessed
by an independent endocrinologist in order to determine the effect of TMC278 on
steroidogenesis within the adrenal gland and the gonads. From the clinical data it was
concluded that TMC278 25 mg once daily does not have a clinically relevant effect on
adrenal function in HIV-infected adult subjects. A White Paper on the endocrine safety
evaluation of TMC278 is presented in Module 5.4, TMC278 20100630 Expert
Endocrinology.
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Final
In conclusion, none of these changes, investigated and described in considerable detail, are
considered to be clinically relevant. There were no clinical signs or symptoms suggestive of
an adrenal or gonadal dysfunction.
Endocrine events of interest, including events related to adrenal insufficiency, are discussed
in Section 2.5.5.11.2.
2.5.5.2.3.2.7.
Adverse Drug Reaction Analysis in Pooled Phase 3 Trials of TMC278
Adverse Drug Reactions (ADRs) are AEs that are considered at least possibly related to the
use of a drug substance. Adverse drug reactions, rather than treatment-emergent AEs, are
identified to facilitate communication of possible drug-associated risks within prescribing
information.
In order to identify AEs as ADRs, data from the 35 trials included in the Summary of Safety
were analyzed and reviewed in accordance with company methodology, as detailed in
Module 2.7.4, Appendix 2.7.4.7.3, Appendix 12.10.1.
A complete list of AEs identified as ADRs is presented in Module 5.3.5.3,
TMC278-C904-Anal-ADD, Display ADD.5. An overview of AEs not considered to be
ADRs is presented in Module 5.3.5.3, TMC278-C904-Anal-ADD, Display ADD.8.
A tabulation of all ADRs, regardless of grade, reported during 48-week treatment with
TMC278 or control is provided in Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.2,
Table 113. ADRs related to laboratory abnormalities are excluded from this table and are
described in detail in Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.3.
In general, the proportion of subjects experiencing at least one ADR in the Phase 3 trials was
lower in the TMC278 group (51.6%) compared with the control group (67.9%). The majority
of ADRs reported were Grade 1 or 2 in severity. Grade 3 or 4 ADRs occurred in 3.1% and
5.6% of TMC278- and control-treated subjects, respectively. Serious ADRs were
infrequently reported, with very low incidences in the 2 treatment groups (4 subjects [0.6%]
with TMC278 and 8 subjects [1.2%] with control). There were no serious ADRs with an
outcome of death. The proportion of subjects experiencing ADRs leading to permanent
discontinuation of study medication was 1.6% in the TMC278 group and 4.0% in the control
group.
Adverse drug reactions of at least Grade 2 did not occur frequently with TMC278. The most
common ADRs (in at least 2.0% of subjects) with at least Grade 2 severity reported with
TMC278 treatment were depression (3.5% on TMC278 versus 2.2% on control), insomnia
(2.9% versus 3.2%), headache (2.6% versus 3.4%) and rash (2.2% versus 9.4%). The greatest
differences between the treatment groups in the incidence of ADRs of at least Grade 2 were
seen for rash (2.2% on TMC278 versus 9.4% on control) and dizziness (0.7% versus 6.6%).
Individual Grade 3 and/or 4 ADRs were reported in at most 2 subjects in the TMC278 group.
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Overall, the percentage of subjects reported with an ADR leading to discontinuation was low
in both treatment groups. A slightly smaller proportion of subjects in the TMC278 group
(1.2%) experienced at least 1 ADR leading to discontinuation when compared to the control
group (3.2%). In the TMC278 group, all ADR grouped terms leading to permanent
discontinuation had an incidence below 0.5%. By grouped term, the most common ADRs
leading to discontinuation in the control group were rash (1.5%), depression (0.6%) and
abnormal dreams (0.6%).
There were no additional preferred terms identified as ADRs from the Phase 1, Phase 2a and
Phase 2b trials that were not already listed from the pooled Phase 3 ADR analysis.
No clinically important differences were revealed in the comparison of the incidence of AEs
(regardless of causality), in the AEs considered at least possibly related in the opinion of the
investigator, and in ADRs. It can be concluded that the presentation of ADRs in the full
prescribing information of TMC278 represents a complete and accurate safety and
tolerability profile of the product based on the cumulative available safety data.
2.5.5.2.4.
AE Data to Support the FTC/RPV/TDF FDC Tablet
The adverse reactions considered at least possibly related to treatment with the components
of the FTC/RPV/TDF FDC tablet from clinical trial data (as detailed above for FTC, RPV,
and TDF) and postmarketing experience (for FTC and TDF) are listed in Table 25, below, by
body system organ class and frequency. Within each frequency grouping, undesirable effects
are presented in order of decreasing seriousness. Frequencies are defined as very common
(t 1/10), common (t 1/100 to < 1/10), uncommon (t 1/1,000 to < 1/100) or rare (t 1/10,000
to < 1/1,000).
The safety assessment of RPV is based on pooled data from 686 patients who received RPV
25 mg once daily in the Phase 3 trials C209 and C215 (see Section 2.5.5.2.3.2.7). Clinical
ADRs of at least moderate intensity (t Grade 2) and selected treatment-emergent clinical
laboratory abnormalities, considered as ADRs for RPV, are summarized in Table 25.
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Table 25.
Final
Tabulated Summary of Adverse Reactions Associated with the Individual Components of the
FTC/RPV/TDF FDC Tablet Based on Clinical Study and Postmarketing Experience
Frequency
RPVa
FTC
TDF
Blood and lymphatic system disorders:
Common:
neutropenia
decreased white blood cell count
—
Uncommon:
anaemiab
decreased hemoglobin, decreased platelet
count
—
—
—
Immune system disorders:
Common:
allergic reaction
Metabolism and nutrition disorders:
Very common:
—
—
Hypophosphataemiac
Common:
hyperglycemia, hypertriglyceridemia
decreased appetite
—
Uncommon:
—
increased total cholesterol (fasted),
increased LDL cholesterol (fasted),
increased triglycerides (fasted)
Hypokalaemiac
Rare:
—
—
lactic acidosis
Common:
insomnia, abnormal dreams
depression, insomnia, abnormal dreams,
sleep disorders
—
Uncommon
—
depressed mood
Psychiatric disorders:
Nervous system disorders:
Very common:
headache
—
dizziness
Common:
dizziness
headache
headache
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Frequency
Uncommon
Final
RPVa
FTC
—
TDF
dizziness, somnolence
—
Gastrointestinal disorders:
Very common:
diarrhoea, nausea
—
diarrhoea, vomiting, nausea
Common:
elevated amylase including elevated
pancreatic amylase, elevated serum lipase,
vomiting, abdominal pain, dyspepsia
increased pancreatic amylase, abdominal
pain, nausea
abdominal pain, abdominal distension,
flatulence
Uncommon:
—
increased lipase, vomiting, abdominal
discomfort
pancreatitis
Hepatobiliary disorders:
increased transaminases (AST and/or ALT)
Common:
elevated serum aspartate aminotransferase
(AST) and/or elevated serum alanine
aminotransferase (ALT),
hyperbilirubinemia
Uncommon
—
increased bilirubin
—
Rare:
—
—
hepatic steatosis, hepatitis
rash
increased transaminases
Skin and subcutaneous disorders:
Very common:
—
—
rash
Common:
vesiculobullous rash,
pustular rash, maculopapular rash, rash,
pruritus, urticaria, skin discoloration
(increased pigmentation)b
Uncommon:
angioedemad
—
angioedema
—
—
—
Musculoskeletal and connective tissue disorders:
Very common:
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Frequency
Final
RPVa
FTC
TDF
c
Uncommon:
—
—
Rhabdomyolysis , muscular weaknessc
Rare:
—
—
osteomalacia (manifested as bone pain and
infrequently contributing to fractures)c,d,
myopathyc
—
increased creatinine, proteinuria
—
renal failure (acute and chronic), acute
tubular necrosis, proximal renal tubulopathy
including Fanconi syndrome, nephritis
(including acute interstitial nephritis)d,
nephrogenic diabetes insipidus
Renal and urinary disorders:
Uncommon:
Rare:
—
—
General disorders and administration site conditions:
Very common:
—
—
asthenia
Common:
pain, asthenia
fatigue
—
a
b
c
d
Only adverse reactions of moderate intensity (Grade 2 to 4 for adverse reactions and Grade 3 to 4 for laboratory abnormalities) are included for RPV.
Anaemia was common and skin discoloration (increased pigmentation) was very common when FTC was administered to pediatric patients.
This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with TDF in the absence of this condition.
This adverse reaction was identified through postmarketing surveillance but not observed in randomized, controlled clinical trials in adults or pediatric HIV clinical trails for
FTC or in randomized controlled clinical trials or the TDF expanded access program for TDF. The frequency category was estimated from a statistical calculation based on
the total number of patients exposed to FTC in randomized controlled clinical trials (n = 1,563) or TDF in randomized controlled clinical trials and the expanded access
program (n = 7319).
Source: RPV: Module 2.7.4, Appendix 2.7.4.7.3, Section 9.1.2, Table 114 and Module 2.7.4, Appendix 2.7.4.7.3, Section 12.5, Table 120; FTC and TDF: SmPC for Truvada
(EPAR-Product Information, last updated 16/2/2010)
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2.5.5.3.
Final
Renal Adverse Events
Renal adverse events are described in Module 2.7.4.2.1.5.2. Creatinine and eGFRcreat changes
were analyzed in the Phase 3 trials, and eGFRcyst was analyzed in trial C215, overall and by
background regimen (see Section 2.5.5.2.3.2.4). The results of the analysis of cystatin C
performed in trial C215 are also described in an addendum to the CRR (Module 5.3.5.1,
TMC278-C215-W48-CRR-Add).
Renal excretion by a combination of glomerular filtration and tubular secretion is also the
primary route of elimination of FTC. Preclinical testing of FTC did not detect evidence of
kidney toxicity even at very high doses.
No data are currently available for TMC278 in patients with renal impairment. Since the
renal clearance of TMC278 is negligible (< 1% of total), a decrease in total body clearance is
not expected in patients with renal impairment. No dose adjustment is required for renally
impaired subjects.
The primary route of elimination of TFV is renal excretion by a combination of glomerular
filtration and tubular secretion. Nonclinical studies of TFV at exposures similar to or
2- to 20-fold higher than that achieved in humans after a 300-mg daily dose detected some
evidence of mild nephrotoxicity in the dog, rat, and monkey. In addition, nephrotoxicity is
the dose-limiting toxicity associated with the clinical use of other nucleotide compounds in
this class, i.e., cidofovir and high doses of adefovir dipivoxil (60 mg and 120 mg) evaluated
for HIV disease. Long-term safety data from clinical trials of TDF do not demonstrate a
causal association between renal events and TDF therapy. However, postmarketing safety
data indicate that TDF therapy may cause renal adverse reactions, including renal failure,
Fanconi syndrome and other proximal tubulopathies.
The following sections summarize the principal renal safety data from clinical studies of
TDF, the renal toxicity profile during postmarketing experience, potential mechanisms of
renal toxicity and risk factors for renal dysfunction.
2.5.5.3.1.
Renal Safety in Clinical Studies
In long-term clinical studies of TDF in HIV-1 infected subjects, renal safety was determined
based on clinical AEs and laboratory measures of renal function, specifically changes in
serum creatinine and phosphorus, and calculated CLcr (Cockcroft-Gault equation). Subjects
participating in these studies had to have adequate renal function at baseline (typically CLcr
t 60 mL/min, or t 50 mL/min in Study GS-01-934), and could not receive drugs that are
nephrotoxic, have nephrotoxic potential, or compete for active renal elimination. The
principal Gilead clinical studies of TDF and the main findings related to renal safety are
summarized in Table 26.
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Table 26.
Final
Summary of Gilead Clinical Studies that Assessed Renal Safety in
HIV-1 Infected Subjects Receiving TDF
Clinical
Study
Principal
Dataset
Evaluated
Study Design
Regimen
GS-99903
Randomized, double
blind, activecontrolled,
equivalence study in
antiretroviral-naive
subjects, 144-week
double-blind period
and 336-week openlabel ext.
TDF + 3TC +
EFV (n = 299)
d4T + 3TC +
EFV (n = 301)
144 weeks
Acute renal failure occurred in
2 subjects (one each in 2 groups),
both unrelated to drugs, and led to
discontinuation of 1 subject in the
d4T group; graded serum creatinine
elevation: TDF = 13 subjects (4%, 0
Grade 3); d4T = 9 subjects (3%, 2
Grade 3); graded hypophosphatemia:
TDF = 22 subjects (7%, 1 Grade 3);
d4T = 19 subjects (6%, 2 Grade 3).
GS-01934
Randomized, 144week, open-label,
active-controlled,
study in treatmentnaive subjects,
followed by 96-week
single-treatment
phase
TDF + FTC +
EFV (n = 257)
Combivir +
EFV
(n = 254)
144 weeks
Nephrolithiasis, unrelated to study
drugs, occurred in 4 subjects in the
TDF group, and 2 subjects in the
Combivir group. Acute renal failure
for 1 subject in the Combivir group,
unrelated to study drugs. Mild renal
impairment for 1 subject in the TDF
group, related to study drugs.
Confirmed (on 2 consecutive visits)
graded serum creatinine elevation:
TDF = 1 subject (Grade 1); Combivir
= 2 subjects (Grade 2); confirmed
graded hypophosphatemia: TDF =
1 subject (Grade 2), Combivir = 2
subjects (Grade 2)
GS-98902
Randomized (2:2:2:1)
placebo-controlled
study in treatmentexperienced subjects,
blinded through
Week 48
HAART +
TDF 75 mg
(n = 54),
150 mg
(n = 51),
300 mg
(n = 56), or
placebo
(n = 28)
24 and
48 weeks
Through 48 weeks, 2 subjects (1%)
in TDF group had a renal AE t
Grade 3 (1 subject nephrolithiasis,
1 subject pyelonephritis, both in
initial 24 weeks), versus none in the
placebo group. Graded serum
creatinine: TDF = 2 subjects (4%),
placebo = 1 subject (1%) (all
Grade 1); graded hypophosphatemia
through 24 weeks: TDF = 24 subjects
(15%, 1 Grade 3); placebo =
1 subject (4% Grade 2)
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Main Renal Outcome
18AUG2010
Clinical
Study
Study Design
Regimen
Final
Principal
Dataset
Evaluated
Main Renal Outcome
GS-99907
Randomized (2:1),
placebo-controlled
study in treatmentexperienced subjects,
24-week double-blind
period and 24-week
open-label extension
HAART +
TDF 300 mg
(n = 368)
or
placebo
(n = 182)
24 and
48 weeks
Through the blinded 24-week period,
2 subjects in TDF group had a renal
AE t Grade 3 (nephrolithiasis).
Through 48 weeks, a total of 4 cases
of nephrolithiasis occurred versus
none in placebo group. Graded serum
creatinine: TDF = 6 (2%); placebo =
2 (1%), all Grade 1; graded
hypophosphatemia: TDF =
55 subjects (15%, 1 Grade 4);
placebo = 15 subjects (8%, 1
Grade 3)
GS-99910
Rollover protocol
from GS-98-902
(n = 102),
GS-99-907
(n = 465),
and GS-97-901
(n = 6)
HAART +
TDF 300 mg
(n = 573)
2.3 years
(mean
dosing
period)
2 subjects discontinued due to renal
events, 1 subject with renal
insufficiency, 1 subject with Fanconi
syndrome; graded serum creatinine:
45 subjects (8%, all Grade 1); graded
hypophosphatemia: 131 subjects
(23%, 6 subjects Grade 3, 1 subject
Grade 4), most transient & resolved
without phosphate supplementation
There was no evidence of renal toxicity during 2 long-term, controlled studies in
antiretroviral-naive subjects that compared NNRTI-based regimens containing TDF with
control regimens (144 weeks of follow-up in Studies GS-99-903 and GS-01-934). Overall,
few graded serum creatinine or serum phosphorus abnormalities were observed in the TDF or
control groups in either study. There was no evidence that continued dosing of TDF led to
progression from Grade 1 renal abnormalities to more severe grades. During 144 weeks of
treatment in Study GS-99-903, 2 subjects in the TDF group and 1 subject in the d4T group
had an episode of renal failure or renal insufficiency that was reported as an SAE. Neither of
the TDF cases was considered related to treatment. In Study GS-01-934, there was a small
but statistically significant decrease from baseline to Week 144 in estimated glomerular
filtration rate for the FTC + TDF group; the significance of this change is unknown. No cases
of Fanconi syndrome were reported, and no subjects in the TDF groups permanently
discontinued study medication due to a renal abnormality. Further long-term data available
from up to 240 weeks in Study GS-99-903 continue to support a lack of effect of TDF on
renal function.
The safety and efficacy profile of TDF in HIV-1 infected subjects with mild renal
impairment has been characterized based on a pooled subset of subjects (n = 28) who
participated in Studies GS-99-903 and GS-01-934 and whose baseline calculated CLcr was
t 50 mL/min to < 80 mL/min. The results demonstrated a similar safety and efficacy profile
in subjects with mild renal impairment compared with subjects with normal renal function in
Studies GS-99-903 and GS-01-934.
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Through 144 weeks in Studies GS-99-903 and GS-01-934, no clinically relevant changes in
renal function were seen in black subjects, subjects t 50 years old, subjects with mild renal
impairment, or in subjects taking antihypertensive or antidiabetic medications {12702}.
These findings support the use of TDF 300 mg once daily, in combination with other
antiretroviral regimens in HIV-1 infected subjects with a calculated CLcr t 50 mL/min.
Similarly, in antiretroviral-experienced subjects, renal toxicity was not identified during the
placebo-controlled studies, GS-98-902 and GS-99-907, and during the rollover, long-term,
extension study, GS-99-910, with a median duration of follow-up of 2.3 years. The 24-week
placebo-controlled pooled data analysis of Studies GS-98-902 and GS-99-907 demonstrated
that the incidence of elevations in serum creatinine was similar for the placebo and TDF
groups (1% in both groups). The incidence of hypophosphatemia in the TDF group was
slightly higher than in the placebo group (13% versus 8% of subjects). With long-term
follow-up in the extension study, the rate of occurrence of hypophosphatemia in subjects
treated with TDF did not increase over time. In most cases, hypophosphatemia (< 2.0 mg/dL)
was transient and resolved with continued TDF dosing without need for phosphate
supplementation {6137}.
The renal safety of TDF when administered in combination with PIs has been reported from
2 controlled studies, Abbott Study M02-418 in antiretroviral-naive subjects and
Bristol-Myers Squibb Study AI424045 in antiretroviral-experienced subjects. In these
studies, HIV-1 infected subjects received TDF in PI-based regimens that included LPV/r or
atazanavir, respectively. When coadministered with TDF, LPV/r and atazanavir increase the
systemic exposure to TFV by 32% and 24%, respectively (also see Section 2.5.3.4.3).
Therefore, AE experience with these regimens is of particular importance for the assessment
of renal safety. During 96 weeks of follow-up, the renal safety profile was consistent with the
Gilead-sponsored studies {7974}, {6134}, {7358}, {7374}.
In summary, results from long-term, controlled efficacy and safety studies of TDF in
HIV-1 infected subjects have not demonstrated an increased risk of renal events in subjects
on TDF therapy.
2.5.5.3.2.
Experience in Postmarketing Surveillance
Although clinical trial safety data do not indicate a causal association between TDF therapy
and renal events, postmarketing drug safety surveillance data have indicated that TDF may
cause renal adverse reactions (see Module 2.7.4.6). These reactions include acute renal
failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy,
interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal
insufficiency, increased creatinine, proteinuria, and polyuria. The incidence and severity of
these renal events are expected to be dose-related, based on the current understanding of the
mechanism of renal toxicity, as well as experience with cidofovir and adefovir dipivoxil.
The following adverse reactions may occur as a consequence of proximal renal tubulopathy:
rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently contributing to
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Final
fractures), hypokalemia, muscular weakness, myopathy, and hypophosphatemia. These
events are not considered to be causally associated with TDF therapy in the absence of
proximal renal tubulopathy.
2.5.5.3.3.
Mechanisms of Renal Toxicity
A range of in vitro studies have been conducted to characterize the potential of TFV for renal
toxicity.
As a part of these studies, the effects of TFV on the growth and viability of normal human
renal proximal tubule cells (RPTECs) were evaluated and compared with those of 2 related
acyclic nucleotide analogs, cidofovir and adefovir {2520}. Tenofovir demonstrated markedly
less cytotoxicity in RPTECs compared with adefovir and cidofovir, a finding consistent with
the relative potential of the 3 nucleotide analogs to cause renal tubular dysfunction in vivo.
Evidence of mitochondrial damage on electron microscopy (EM) in renal tubules has been
observed from limited data in patients experiencing TDF-associated renal dysfunction and in
animals treated with TDF, although no conclusions can be drawn on whether the observed
EM findings of morphologic mitochondrial damage are a cause or effect of TDF-associated
renal dysfunction {9005}, {10960}, {12007}, {13786}, {14196} . In contrast with other
NRTIs (ddI, d4T, or zalcitabine), TFV does not affect the replication of mitochondrial DNA
in human RPTECs in vitro (Report P1278-00042 and {3320}, {9864}). This observation is
consistent with the weak inhibition of DNA polymerase J by tenofovir diphosphate and
indicates that TFV-associated renal dysfunction is unlikely to be a direct consequence of
mitochondrial toxicity due to the inhibition of DNA polymerase J {3320}, {9864}.
As described in Section 2.5.3.4.1, results of in vitro transport studies indicate that the active
tubular secretion of TFV is principally mediated by hOAT1 and MRP4 acting in series as the
major uptake and efflux transporters, respectively, in the proximal tubule. Data from
extensive in vitro drug interaction studies using the identified transporters indicate a low
potential of PIs to affect TFV renal secretion and/or its accumulation in the proximal tubule,
with consequential changes in the renal safety profile of TDF. (Gilead Report Nos.
PC-104-2010, PC-104-2011 and PC-104-2018 and PC-104-2019) {8418}, {9863}, {9864}.
The results of these studies do not provide evidence to support an interaction between HIV
protease inhibitors and TFV during the active tubular secretion of TFV.
Recent data indicate that intestinal drug-drug interactions between TDF and some frequently
used PIs may occur during the process of TDF intestinal absorption {8904}, {11255},
{10610}, {10611}.
In contrast to the lack of involvement of MRP2 in the renal tubular efflux of TFV concluded
from in vitro studies, the findings of a published study (in MRP2 deficient rats and in rats
treated with probenecid) {8646}, and pharmacogenomics studies {10259}, {14978} propose
a potential modulatory effect of MRP2 on TFV exposure and excretion. The results from
these small exploratory studies are not considered as conclusive evidence for the association
between any specific transporter genotype and TFV-related renal adverse events.
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Furthermore, the studies come to conflicting conclusions about the importance of various
single-nucleotide polymorphisms (SNPs) in MRP2 {14978}, {10259}. A further study found
a SNP in MRP4 that they believed correlated with changes in TFV pharmacokinetics (renal
clearance and intracellular tenofovir diphosphate concentrations) but did not find a
correlation with either of the MRP2 SNPs {12344}, {12230}.
The authors from one in vitro study suggested that MRP7 may also play a role in the
elimination of TFV from renal tubular cells {15430}. However, the physiological relevance
of these preliminary findings is unclear including the assessment of the role of MRP7 relative
to MRP4 in the renal efflux of TFV.
Although the molecular mechanism of TFV associated renal dysfunction is not fully
understood at the present time, it is plausible that this adverse effect might be a consequence
of disrupted transport equilibrium between the tubular uptake and efflux of TFV due to
genetic polymorphism in renal transporters.
2.5.5.3.4.
Risk Factors
Based on the renal excretion of TFV, the main risk factors with respect to the development of
renal dysfunction are pre-existing renal disease and concurrent administration of nephrotoxic
agents. The potential for investigating risk factors for renal toxicity from the clinical trial
database is limited due to the small number of cases of renal AEs and entry criteria
necessitating adequate renal function at baseline and excluding concomitant nephrotoxic
medications. In a published analysis, a subset of subjects in Study GS-99-903 were identified
as taking concomitant antihypertensive and/or diabetes drugs during the study (68 subjects,
28 of whom received TDF). Analysis of the glomerular filtration rate (Cockcroft-Gault
equation) for this subgroup showed no significant changes from baseline to Week 144
{8414}.
Large observational cohort studies with long periods of follow-up have utility for further
assessing the postmarketing experience on a population basis and are particularly suitable for
the assessment of potential risk factors for TDF-associated renal toxicity. A number of
analyses of cohort databases (including Johns Hopkins HIV clinic cohort, the Chelsea and
Westminster HIV cohort, and the CHORUS study) and expanded access programs have
reported the effect of TDF on renal function and associated risk factors {7672}, {7987},
{6772}, {8056}, {7625}, {8344}, {7725}, {7987}, {8715}, {9023}, {9161}, {9334}, {10394}.
These studies indicate that the incidence of renal dysfunction in patients receiving
antiretroviral regimens that include TDF is low and similar to that in regimens without TDF.
The most frequently identified predictors for development of renal events were pre-existing
renal disease, concurrent administration of nephrotoxic agents, and advanced HIV disease
with low CD4 cell counts. Serious comorbid conditions such as severe intercurrent illness,
severe hypertension, and diabetes mellitus were not consistently identified as predictors for
TDF-associated renal dysfunction. In several studies, use of PIs or LPV/r was not associated
with an increased risk of renal dysfunction. In the EuroSIDA cohort study, a large
prospective nonrandomized cohort study, older age, hypertension, hepatitis C coinfection,
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lower baseline eGFR and CD4 count were independently associated with increased risk of
chronic kidney disease in patients who started TDF {15280}.
Additionally, in TDF expanded access programs, data indicate that risk factors for increased
serum creatinine included low CD4 cell count, older age, low baseline body weight, higher
baseline serum creatinine concentration, and concomitant nephrotoxic medications; however,
coadministration of LPV/r was not a risk factor {7725}, {10921}.
Patients who have previously experienced renal events while receiving other nucleotide
analogues, such as adefovir dipivoxil, may be at an increased risk of developing renal
toxicity on TDF given the similar structure of these drugs and renal toxicity profiles.
2.5.5.3.5.
Conclusions on Renal Safety
Long-term safety data from clinical trials do not demonstrate a causal association between
renal events and TDF therapy. Postmarketing safety data indicate that TDF therapy may
cause renal adverse reactions. These reactions include acute renal failure, renal failure, acute
tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis
(including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased
creatinine, proteinuria, and polyuria. The following adverse reactions may occur as a
consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as
bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness,
myopathy and hypophosphatemia. These events are not considered to be causally associated
with TDF therapy in the absence of proximal renal tubulopathy. Renal safety data for TDF
remain under close monitoring.
In order to further evaluate whether the effect of TMC278 on serum creatinine cystatin C was
measured in subjects in the C215 trial at baseline, Week 2 and Week 24 (see
Section 2.5.5.2.3.2.4). The results of this analysis show a small mean increase in eGFRcyst in
the TMC278 group at Week 2 and at Week 24. The increase in eGFRcyst was seen in all
subgroups by background regimen, at Week 2 and at Week 24, with TMC278 and with
control. These data indicate that there is no TMC278-induced nephrotoxicity.
The proposed FTC/RPV/TDF FDC tablet prescribing information contains guidance in
relation to the management of the risk of renal toxicity. Specifically, the guidance details the
renal safety profile of TDF and the recommendations for monitoring of renal function,
particularly in at-risk populations and states that the use of the FDC tablet cannot be
recommended in patients with moderate to severe renal impairment (CLcr < 50 mL/min) as
they require dosing interval adjustment that cannot be achieved with the FTC/RPV/TDF FDC
tablet.
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2.5.5.4.
Final
Effects on the Skin
Skin adverse events are described in Module 2.7.4.2.1.5.3.
2.5.5.4.1.
Emtricitabine
Skin discoloration, reported as hyperpigmentation and usually affecting either the palms of
the hands or the soles of the feet, or both, has been reported in HIV-1 infected patients
treated with FTC. Most of the hyperpigmentation events were asymptomatic, and nearly all
of the events were assessed by the investigator as being mild in severity. The skin
discoloration was very common when FTC was administered to pediatric patients. The
mechanism and clinical significance of the hyperpigmentation associated with FTC are
unknown. Events of hyperpigmentation continue to be monitored during postmarketing
surveillance.
2.5.5.4.2.
Rilpivirine
Certain skin events are side effects commonly observed with drugs of the NNRTI class and
are therefore closely monitored in all clinical trials with TMC278.
For the Phase 3 pooled analysis and the Phase 2b analysis, based on the list of preferred
terms occurring across all trials, a list of events to be considered as skin events of interest
was created and an “alternative grouping” was used (refer to Module 2.7.4,
Appendix 2.7.4.7.3, Section 1.3.2.4.1 for details).
The most common skin event of interest was rash (a grouped term including any type of rash)
in both the TMC278 and control groups. The incidence of other skin events of interest was
low without substantial difference between the treatment groups. Dermatitis/eczema
(grouped term) was reported at a somewhat higher incidence on TMC278 than on control
(4.7% versus 2.3%, respectively).
Rash (grouped term, regardless of causality) was reported with a significantly lower
incidence in the TMC278 group compared to the control group (7.4% vs 22.0%) (p < 0.0001,
Fisher exact test). The majority of rashes were Grade 1 or 2 in severity and there were no
Grade 4 rashes. Grade 3 rashes were reported by 2 subjects (0.3%) in the TMC278 group
versus 5 subjects (0.7%) in the control group.
The incidence of any rash was highest in the first 4 weeks, consistent with other drug-related
rashes, with a much lower incidence in the TMC278 group than the control group. Few new
rash events occurred thereafter, and with comparable incidence in the TMC278 and control
groups. More rashes led to permanent discontinuation in the control group (11 subjects [1.6%]
than in the TMC278 group (1 subject [0.1%]). Rashes not leading to disconintuation mostly
resolved.
Treatment-related rash (grouped term) is summarized in Table 27.
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Table 27.
Final
Rilpivirine Trials C209 and C215: Treatment-Related Rash
(Grouped Term) Summary (Phase 3 Week 48 Pooled Analysis)
TMC278
N = 686
Control
N = 682
Any, n (%)
21 (3.1)
93 (13.6)
Grade 1
17 (2.5)
42 (6.2)
Grade 2
6 (0.9)
52 (7.6)
Grade 3
1 (0.1)
5 (0.7)
14
10.5
(1 - 407)
55
11.0
(1 - 280)
17
17.0
(3 - 96)
57
10.0
(1 - 470)
Leading to permanent stop, n
(%)
1 (0.1)
11 (1.6)
Leading to temporary stop, n
(%)
1 (0.1)
15 (2.2)
AE Summary
Time of first onset (days)
Number of eventsa
Median
(range)
Duration (days), n
Number of eventsa
Median
(range)
a
For ‘Time to onset’, only the first treatment-emergent event is counted. For ‘Duration’, all treatment-emergent events
are counted (i.e., a subject can be counted twice)
Treatment related defined as possibly, probably, or very likely related to treatment in the opinion of the investigator.
Treatment-related rash (grouped term) was reported at a lower incidence in the TMC278
group (3.1%) than in the control group (13.6%). The difference in incidence was statistically
significant in favor of TMC278 (p < 0.0001; Fisher exact test). The median time to onset of
treatment-related rash was similar in the TMC278 group and control group (10.5 and
11.0 days, respectively), while the median duration of treatment-related rash was longer on
TMC278 (18 days) than on control (10 days).
In the TMC278 group, 2 subjects had Grade 3 rashes during treatment with TMC278, of
which one was very likely related to TMC278 and led to permanent discontinuation. In the
control group, 5 subjects had Grade 3 rashes. All 5 AEs were judged by the investigator to be
very likely related to study medication and led to discontinuation.
Overall, 1 subject (0.1%) discontinued the trial due to treatment-related rash in the TMC278
group, compared to 11 subjects (1.6%) in the control group.
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2.5.5.4.3.
Final
Tenofovir DF
Rash has been identified as an adverse drug reaction to TDF in postmarketing experience.
However, skin effects are not considered to be an important safety concern for TDF.
2.5.5.4.4.
FTC/RPV/TDF FDC Tablet
The proposed FTC/RPV/TDF prescribing information includes the term “rash” as a very
common adverse reaction. The following are included as “common adverse reactions”:
x
Rash, vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria,
and skin discoloration (increased pigmentation)
2.5.5.5.
Effects on the Bone
Bone adverse events are described in Module 2.7.4.2.1.5.1.
2.5.5.5.1.
Emtricitabine
FTC is not considered to have any effects on bone safety. In preclinical studies of FTC, no
effects on bone were observed.
2.5.5.5.2.
Rilpivirine
RPV is not considered to have any affects on bone safety.
2.5.5.5.3.
Tenofovir DF
In preclinical toxicology studies of TDF, bone abnormalities were reported in the juvenile
macaque/simian immunodeficiency virus model at subcutaneous doses of 30 mg/kg/day
(i.e., systemic exposure approximately 25-fold higher than human exposure). The
abnormalities included reduced BMD, joint swellings, and bone fractures. Elevated alkaline
phosphatase activity, decreased serum phosphorus concentration, glucosuria, and proteinuria
were also observed in the macaques with bone lesions; serum calcium values were normal.
Discontinuation of treatment or reduction of the dose to 10 mg/kg/day or less was associated
with resolution of the bone abnormalities and biochemical changes. Preclinical studies that
investigated potential mechanisms for direct or indirect effects of TFV on bone provided no
evidence of in vitro and in vivo cytotoxicity to bone. The mechanism underlying this bone
toxicity is unknown. An assessment of the clinical data related to bone toxicity in adult
HIV-1 infected subjects is presented below.
The 144-week safety database of Study GS-99-903 provides the largest, prospective,
centrally analyzed evaluation of bone-related parameters in previously untreated
HIV-1 infected subjects. No increased risk of bone factures was observed during the
144-week double-blind treatment period. At Week 144, there were small decreases from
baseline in BMD of the lumbar spine and hip in both treatment groups. There was a greater
mean percentage decrease from baseline in BMD at the lumbar spine with the TDF regimen
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compared with the d4T regimen (2.2% TDF versus 1.0% d4T, p 0.001). Changes in
BMD at the hip were similar between the 2 treatment groups (2.8% TDF versus 2.4% d4T,
p = 0.064). The majority of the changes in BMD occurred in the first 24 weeks of the study
for the spine and in the first 48 weeks of the study for the hip. There was little or no
progression in loss of BMD for the remainder of the study. Since there is no evidence of an
increased risk in bone fractures during 144 weeks of treatment, these small nonprogressive
reductions in BMD are not considered to be clinically relevant.
Through Week 144, markers of both bone formation (serum osteocalcin and bone-specific
alkaline phosphatase) and bone resorption (urinary N-telopeptide and serum C-telopeptide)
demonstrated greater and significant changes in the TDF group compared with the d4T
group. The mean changes from baseline appeared to peak at Week 48 and then were lower at
Week 96 through Week 144, consistent with the nonprogressive changes seen on bone
densitometry after Week 48. Overall, there appeared to be a transitory increase in bone
remodeling in the TDF subjects; however, a new equilibrium was reached without evidence
of imbalance between bone formation and bone resorption.
The incidence of osteopenia and osteoporosis in the spine were evaluated at baseline and at
Week 144 in Study GS-99-903 using the World Health Organization criteria (T-score 2.5 to
1.0 for osteopenia and T-score 2.5 for osteoporosis) {8115}. A relatively high proportion
of this study population (approximately 25% to 30%) had spine osteopenia and osteoporosis
at baseline compared with an expected value of 16% in a normal population, confirming
other literature reports that bone loss may be a consequence of HIV-1 infection itself. There
were no significant differences in the incidences of osteopenia and osteoporosis in the spine
between the TDF and d4T groups either at baseline or at Week 144. Neither were there any
significant differences between the treatment groups in terms of progression to osteopenia or
osteoporosis.
For the subset of subjects who continued TDF during the extension phase of
Study GS-99-903, interim data following 96-weeks of open-label treatment confirm that the
majority of the change occurred in the first 24 to 48 weeks of the study with little or no
progression in loss of BMD for the remainder of treatment through Week 240. A small
percentage decrease (0.7%) in spine BMD was observed in the subset of subjects who
switched from d4T to TDF (the d4T/TDF group) at open-label Week 96, the magnitude of
which is consistent with the decline expected in a normal aging population (0.5% to 1% per
year after age 35) {9115}, {9116}. In the d4T/TDF group, the mean decrease in hip BMD at
Week 96 (2.8%) was slightly higher than for spine BMD. These BMD changes are unlikely
to be of clinical significance, as no subject receiving TDF experienced pathologic fractures
during the 5-year study.
In the antiretroviral-naive population of Study GS-01-934, the evaluation of bone safety
based on the incidence and type of bone fractures was consistent with the experience in
Study GS-99-903, with no clinically significant bone abnormalities observed.
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The incidence rates of bone fractures in clinical studies of treatment-experienced subjects
have been low and do not indicate any increased risk of bone fractures with TDF therapy
even with long-term exposure.
In summary, long-term clinical trial data in antiretroviral-naive and experienced
HIV-1 infected subjects do not indicate that TDF is associated with an increased risk of bone
fractures.
During postmarketing experience, a number of cases of bone AEs have been received;
alternative causes of the bone events have been present in most cases. However, there is
evidence to suggest that osteomalacia (manifested as bone pain and infrequently contributing
to fractures) may occur as a result of TDF–associated proximal tubulopathy in some reports.
Osteomalacia occurring in the absence of proximal renal tubulopathy is not considered to be
related to TDF.
HIV-1 infection itself is known to be associated with bone disease {6133} and may also be
considered as an alternative cause of bone events in some spontaneous reports.
The assessment of clinical trial data demonstrates minimal risk of bone toxicity with
prolonged administration of TDF. The clinical relevance of the changes in surrogate bone
biomarkers and BMD in antiretroviral-naive subjects has yet to be determined. Osteomalacia,
occurring as a result of TDF–associated proximal tubulopathy, was identified as an adverse
reaction during postmarketing surveillance.
2.5.5.5.4.
The proposed FTC/RPV/TDF prescribing information describes the following in the “Special
warnings and precautions for use” section:
x
In a 144-week controlled clinical study that compared TDF with d4T in combination with
lamivudine and efavirenz in antiretroviral-naive patients, small decreases in bone mineral
density of the hip and spine were observed in both treatment groups. Decreases in bone
mineral density of spine and changes in bone biomarkers from baseline were significantly
greater in the TDF treatment group at 144 weeks. Decreases in bone mineral density of
hip were significantly greater in this group until 96 weeks. However, there was no
increased risk of fractures or evidence for clinically relevant bone abnormalities over
144 weeks.
Bone abnormalities (infrequently contributing to fractures) may be associated with
proximal renal tubulopathy. If bone abnormalities are suspected then appropriate
consultation should be obtained.
2.5.5.6.
Mitochondrial Toxicity and Metabolic Effects
Mitochondrial toxicity adverse events are described in Module 2.7.4.2.1.5.4.
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The major adverse effects of many NRTIs have been linked to mitochondrial toxicity. These
AEs include lactic acidosis, pancreatitis, peripheral neuropathy, lipodystrophy, metabolic
abnormalities, and myopathy. The mechanism of toxicity of NRTIs is thought to result from
inhibition of mtDNA polymerase J, leading to depletion of mtDNA and impaired synthesis of
respiratory chain enzymes. The respiratory chain functions in many metabolic pathways
including adenosine triphosphate synthesis, fatty acid oxidation, and synthesis of pyrimidine
nucleotides {2522}. Therefore, disruption of the respiratory chain may lead to a wide variety
of metabolic and organ system disorders. Mitochondrial toxicity due to NRTIs is
characterized by the following: toxicity is concentration-dependent, the onset of toxicity
requires prolonged exposure and is typically not observed in the first few months of
treatment, and combination therapy with NRTIs may result in additive or synergistic toxicity
{8920}.
NRTIs differ markedly in their propensity to cause mitochondrial toxicity depending on their
ability to interact with mtDNA polymerase J. The results of in vitro studies suggest that
tenofovir diphosphate and FTC-TP have limited capacity to inhibit human DNA polymerases
or to mediate cytotoxicity (see Section 2.5.3.1). US HIV treatment guidelines identify d4T,
ddI, and zidovudine as more strongly associated with severe mitochondrial toxicities than
other NRTIs. As a result, HIV treatment guidelines now recommend using the NRTIs with
less propensity for mitochondrial toxicities, like TDF, FTC, 3TC, and abacavir, when
initiating HAART and as alternate NRTIs for patients who develop mitochondrial toxicities
{15207}. As described below, results from long-term clinical studies of Truvada, FTC, and
TDF confirm a low risk of mitochondrial toxicity with these antiretroviral agents.
2.5.5.6.1.
Emtricitabine
The incidences of AEs of symptomatic hyperlactatemia (including lactic acidosis),
pancreatitis, peripheral neuropathy, and lipodystrophy were assessed across 3 controlled
Phase 3 studies of FTC. The incidences of symptomatic hyperlactatemia and pancreatitis
were uniformly low in the FTC groups of all 3 studies (overall d 1% for the combined FTC
group). In antiretroviral-naive subjects, the incidence of peripheral neuropathy was similar
between FTC- and 3TC-treated subjects (Study FTC-302) and significantly lower than in
d4T-treated subjects (Study FTC-301A). Similarly, the incidence of lipodystrophy in these
studies was 1% in FTC and 3TC groups compared with 6% for d4T. There was a higher
rate of lipodystrophy in antiretroviral-experienced subjects receiving FTC or 3TC in
Study FTC-303, which may have been due to concomitant use of PIs by 80% of subjects and
the longer cumulative duration of antiretroviral therapy (mean duration of prior treatment:
35 months). The overall assessment of these mitochondrial-related AEs in clinical studies
confirms a low risk of mitochondrial toxicity associated with FTC.
2.5.5.6.2.
Rilpivirine
In an in vitro study with RPV, there were no inhibitory effects on human polymerases, Į, ȕ,
or Ȗ (see Module 2.6.2.2.6.2), suggesting a low potential for mitochondrial toxicity. As
mitochondrial toxicity is generally less relevant for NNRTIs than NRTIs, and as RPV is not
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anticipated to significantly increase the exposure of FTC or TFV, the potential for
exacerbating mitochondrial toxicity is low.
2.5.5.6.3.
Tenofovir DF
The assessment of potential mitochondrial toxicities through 144 weeks in the
antiretroviral-naive population of Study GS-99-903 indicates a preferential safety profile
with a TDF regimen compared to a d4T regimen. Through 144 weeks, the combined
incidence of lipodystrophy, lactic acidosis, and peripheral neuritis/neuropathy was
significantly lower in the TDF group than in the d4T group (6% versus 28%; p d 0.001 in all
cases). There were no reports of lactic acidosis in the TDF group versus 3 cases in the d4T
group.
The radiological findings from whole-body, dual-energy x-ray absorptiometry scans were
further indicative of higher rates of lipodystrophy in the d4T group. The mean body
composition in limb fat at Week 144 was significantly greater in the TDF group compared
with the d4T group (8.6 kg vs 4.5 kg, respectively; p 0.001). A similar trend was seen with
respect to abdominal fat, left thigh fat, and trunk fat. During the open-label phase, limb fat
increased slightly in the subset of subjects who continued on TDF (TDF/TDF group) and
increased markedly in the subset of subjects who switched from d4T to TDF (d4T/TDF
group) (from a mean limb fat of 4.6 kg at the start of the open-label phase to 5.5 kg at
open-label Week 96).
Tenofovir DF was associated with smaller mean increases from baseline in fasting lipid
parameters, specifically triglycerides, total cholesterol, and low density lipoprotein
cholesterol, and a greater increase in high density lipoprotein cholesterol compared with the
d4T treatment group following 144 weeks of treatment in Study GS-99-903. In addition,
significantly more subjects commenced first use of a lipid-lowering drug (fibrate acid
derivative and/or statin) in the d4T group than in the TDF group (p 0.001). Data from the
open-label extension phase continue to support the preferential lipid profile of TDF. In the
TDF/TDF group, lipid parameters remained essentially unchanged through Week 240. In the
d4T/TDF group, significant decreases in triglycerides and total cholesterol were observed
from open-label baseline to open-label Week 96.
These findings for subjects receiving TDF and 3TC in combination are considered reflective
of the anticipated profile of the Truvada tablet, given the similarity between 3TC and FTC.
When TDF and FTC were administered in combination in Study GS-01-934, a similar
favorable metabolic profile was observed. The mean increases in fasting serum triglyceride
concentrations and fasting total serum cholesterol concentrations from baseline to Week 144
were significantly smaller for the FTC + TDF + EFV group relative to the CBV + EFV group
(p = 0.047 and p < 0.001, respectively). Additionally, there was a significant increase in
mean body composition in limb fat in the FTC + TDF + EFV group (+1.13 kg change from
Week 48 to Week 144, p < 0.001) compared with a significant decrease in the CBV + EFV
group (1.09 kg change from Week 48 to Week 144, p < 0.001).
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In antiretroviral-experienced subjects, the incidences of pancreatitis, hyperamylasemia,
increased lipase, peripheral neuropathy, and lactic acidosis were similar between subjects
who added TDF or placebo to their standard regimens (Studies GS-98-902 and GS-99-907).
In the few cases of mitochondrial-related AEs that were considered to be possibly related to
TDF (i.e., pancreatitis and lactic acidosis), other risk factors were present, including
concomitant exposure to ddI and/or d4T. During long-term exposure to TDF in
antiretroviral-experienced subjects (Study GS-99-910: mean treatment duration of 2.3 years),
isolated events potentially linked to mitochondrial toxicity occurred in subjects on multidrug
regimens, but there was no evidence that these events were directly linked to TDF.
A number of clinical studies, including GS-MC-164-0111 and GS-DE-164-0106,
demonstrate improvements in metabolic profiles and lipodystrophy in treatment-experienced
subjects switched to TDF-based regimens. Data from the RECOVER study indicate that
switching to TDF improves dyslipidemia and lipoatrophy associated with d4T-based
regimens, while maintaining viral suppression {6074}, {7760}, {7932}. In
Study GS-02-1008, subjects with moderate to severe lipoatrophy who substituted TDF for a
thymidine analog rather than abacavir showed greater improvement in median changes in
metabolic parameters.
Postmarketing Experience
During postmarketing surveillance, AEs potentially associated with mitochondrial
dysfunction are closely reviewed on an ongoing basis for FTC, TDF, and Truvada.
Lactic acidosis, hepatic steatosis and lipodystrophy are important identified risks for both
FTC and TDF, while pancreatitis is an important identified risk for TDF. The exact role of
FTC and TDF in causing these events in humans is unclear due to the presence of concurrent
medications which are also associated with these adverse reactions.
During postmarketing experience, spontaneous cases of lactic acidosis and pancreatitis have
typically involved patients receiving other NRTIs known to be associated with
mitochondrial-related AEs, in particular ddI. Concurrent use of TDF and ddI may increase
ddI-related toxicity because TFV increases systemic exposure to ddI. Pancreatitis and lactic
acidosis are some of the more serious, and potentially fatal, dose-related adverse reactions to
ddI. The EU prescribing information states that coadministration of TDF and ddI is not
recommended.
Evidence of mitochondrial damage on electron microscopy (EM) in renal tubules has been
observed from limited data in patients experiencing TDF-associated renal dysfunction and in
animals treated with TDF, although no conclusions can be drawn on whether the observed
EM findings of morphologic mitochondrial damage are a cause or effect of TDF-associated
renal dysfunction {9005}, {10960}, {12007}, {13786}, {14196}. Tenofovir DF has been
assessed for its potential to cause mitochondrial toxicity in in vivo and in vitro studies. In
vitro studies consistently demonstrated that TDF has a limited capacity to inhibit human
DNA polymerases or to mediate cytotoxicity via inhibition of mitochondrial DNA synthesis.
The mechanism of renal effects remains undefined.
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In summary, the assessment of clinical trial safety data and postmarketing experience to date
demonstrates a low risk of mitochondrial toxicity and metabolic effects with FTC and TDF.
Nonetheless, warning and precaution statements regarding metabolic effects are included in
the proposed prescribing information for the FTC/RPV/TDF FDC tablet as well as the
inclusion of pancreatitis, lactic acidosis, and hepatic steatosis in the Undesirable Effects
section. On the basis of nonclinical and clinical data, FTC and TDF are considered to be less
likely than other NRTIs to cause mitochondrial toxicity, a conclusion supported by current
US HIV treatment guidelines {15207}.
2.5.5.6.4.
x
Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated
in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been
reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or
postnatally to nucleoside analogues. The main adverse reactions reported are
hematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia,
hyperlipasemia). These events are often transitory. Some late-onset neurological
disorders have been reported (hypertonia, convulsion, abnormal behavior). Whether the
neurological disorders are transient or permanent is currently unknown. Any child
exposed in utero to nucleoside and nucleotide analogues, even HIV negative children,
should have clinical and laboratory follow-up and should be fully investigated for
possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings
do not affect current national recommendations to use antiretroviral therapy in pregnant
women to prevent vertical transmission of HIV.
2.5.5.7.
Neurologic Events
2.5.5.7.1.
Emtricitabine
Headache and dizziness have been identified as adverse drug reactions to FTC in clinical
trials. However, neurological effects are not considered to be an important safety concern for
FTC.
2.5.5.7.2.
Rilpivirine
Certain neurologic events are reported to be associated with the use of drugs of the NNRTI
class, especially EFV {15207}, and are therefore closely monitored in all trials with
TMC278. Based on the list of preferred terms occurring across all trials, a list of events to be
considered as neurologic events of interest was created from the SOCs nervous system
disorders, eye disorders, ear and labyrinth disorders, or general disorders and
administration site conditions. The list of preferred terms considered as neurologic events of
interest is presented in Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1.
Neurologic events of interest in the pooled Phase 3 analysis are summarized Table 28.
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Table 28.
Final
Rilpivirine Trials C209 and C215: Neurologic Events of Interest
Summary (Phase 3 Week 48 Pooled Analysis)
AE Summary
TMC278
N = 686
Control
N = 682
Any, n (%)
184 (26.8)
308 (45.2)
Grade 1
165 (24.1)
246 (36.1)
Grade 2
26 (3.8)
81 (11.9)
Grade 3
2 (0.3)
8 (1.2)
Grade 4
1 (0.1)
1 (0.1)
211
402
5.0 (1 - 400)
2.0 (1 - 457)
220
424
12.5 (1 - 519)
15.0 (1 - 581)
117 (17.1)
258 (37.8)
2 (0.3)
1 (0.1)
Leading to permanent stop, n (%)
1 (0.1)
5 (0.7)
Leading to temporary stop, n (%)
2 (0.3)
5 (0.7)
Time of first onset (days)
Number of eventsa
Median (range)
Duration (days)
Number of eventsa
Median (range)
b
Treatment-related AE , n (%)
Any SAE, n (%)
a
For ‘Time to onset’, only the first treatment-emergent event is counted. For ‘Duration’, all treatment-emergent events
are counted (i.e., a subject can be counted twice).
b Defined as possibly, probably, or very likely related to treatment in the opinion of the investigator.
Neurologic events of interest were reported at a lower incidence in the TMC278 group
(26.8%) than in the control group (45.2%) and were reported as treatment-related by the
investigator for a smaller proportion of subjects on TMC278 (17.1%) compared with subjects
on control (37.8%). The difference in incidence was statistically significant in favor of
TMC278, both for any neurologic event of interest and for treatment-related events only
(p<0.0001; Fisher exact test).
The median time to onset for neurologic events of interest was 5 days in the TMC278 group
and 2 days in the control group. The median duration was comparable in each group
(12.5 versus 15.0 days, respectively).
The majority of the neurologic events of interest in TMC278 subjects were Grade 1 or 2 in
severity. Three subjects had Grade 3 or 4 neurologic events of interest during treatment with
TMC278, of which one was probably related to study medication. In the control group,
8 subjects had Grade 3 neurologic events of interest, of which one event worsened to
Grade 4. All these events were considered at least possibly related to treatment.
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Final
The most commonly reported neurologic events of interest were headache (13.8% in the
TMC278 group versus 13.5% in the control group), dizziness, reported at a significantly
lower incidence in the TMC278 group (9.9% in the TMC278 group versus 28.4% in the
control group, p < 0.0001; Fisher exact test) and somnolence (4.1% in the TMC278 group
versus 7.5% in the control group) (Table 29). All other neurologic events of interest were
reported in fewer than 3% of subjects in either group.
Table 29.
Rilpivirine Trials C209 and C215: Neurologic Events of Interest in
at Least 1.0% of Subjects in the TMC278 or Control Group,
Regardless of Severity and Causality (Phase 3 Week 48 Pooled
Analysis)
System Organ Class
Preferred Term, n (%)
TMC278
N = 686
Control
N = 682
Nervous system disorders
175 (25.5)
291 (42.7)
Headache
95 (13.8)
92 (13.5)
Dizziness
68 (9.9)
194 (28.4)
Somnolence
28 (4.1)
51 (7.5)
Disturbance in attention
7 (1.0)
17 (2.5)
10 (1.5)
12 (1.8)
10 (1.5)
11 (1.6)
5 (0.7)
20 (2.9)
5 (0.7)
20 (2.9)
3 (0.4)
7 (1.0)
3 (0.4)
7 (1.0)
General disorders and administration site
conditions
Irritability
Ear and labyrinth disorders
Vertigo
Eye disorders
Vision blurred
Neurologic events of interest were reported at a slightly greater incidence in subjects with a
history of neurologic or psychiatric illness than in subjects with no history, both for TMC278
(34.5% vs 23.1%) and control (49.1% vs 43.4%).
In conclusion, TMC278 appeared to have limited potential for inducing neurologic events,
and this was at a significantly lower rate than in the control group.
2.5.5.7.3.
Tenofovir DF
Dizziness and headache have been identified as adverse drug reactions to TDF in clinical
trials in HIV infected subjects. However, neurological effects are not considered to be an
important safety concern for TDF.
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2.5.5.7.4.
Final
The proposed FTC/RPV/TDF prescribing information includes headache, dizziness and
somnolence as adverse reactions.
2.5.5.8.
Psychiatric Events
2.5.5.8.1.
Emtricitabine
Insomnia and abnormal dreams have been identified as adverse drug reactions to FTC in
clinical trials. However, psychiatric effects are not considered to be an important safety
concern for FTC.
2.5.5.8.2.
Rilpivirine
Certain psychiatric events are reported to be associated with the use of drugs of the NNRTI
class and are therefore closely monitored in all TMC278 clinical trials. All preferred terms
from the SOC psychiatric disorders were considered psychiatric events of interest.
Incidences of psychiatric events of interest, mainly Grade 1 or 2 in severity, were slightly but
significantly lower in the TMC278 group (23.9%) than in the control group (29.0%), and
were reported to be treatment-related by the investigator for a significantly smaller
proportion of subjects on TMC278 (14.9%) than on control (22.7%) (p = 0.0321 and
p = 0.0002, respectively; Fisher exact test).
The median time of onset of psychiatric events of interest was longer in the TMC278 group
(29 days) than in the control group (6 days). The median duration of these events was longer
on TMC278 than on control (76 days versus 53.5 days).
Grade 4 psychiatric events of interest were reported by 3 subjects in the TMC278 group:
suicide attempt (SAE reported as possibly related to study medication by the investigator);
auditory and visual hallucinations (considered doubtfully related to study medication by the
investigator), and alcoholism and major depression (nonrelated SAEs). In the control group,
one subject had Grade 4 bipolar disorder (nonrelated SAE). Grade 3 psychiatric events of
interest were reported for 1.2% and 1.9% of subjects in the TMC278 and control groups,
respectively.
In total, 1.5% and 2.2% subjects in the TMC278 and control groups, respectively,
discontinued due to psychiatric events of interest.
The incidence of psychiatric events of interest in the Phase 3 pooled analysis is summarized
in Table 30.
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Table 30.
Final
Rilpivirine Studies C209 and C215: Psychiatric Events of Interest
in at Least 1.0% of Subjects in the TMC278 or Control Group,
Regardless of Severity and Causality (Phase 3 Week 48 Pooled
Analysis)
System Organ Class
Preferred Term, n (%)
TMC278
N = 686
Control
N = 682
164 (23.9)
198 (29.0)
Insomnia
54 (7.9)
52 (7.6)
Abnormal dreams
46 (6.7)
66 (9.7)
Depression
40 (5.8)
32 (4.7)
Anxiety
16 (2.3)
35 (5.1)
Nightmare
16 (2.3)
26 (3.8)
Sleep disorder
11 (1.6)
24 (3.5)
Depressed mood
7 (1.0)
5 (0.7)
Psychiatric disorders
The most commonly reported psychiatric events of interest on TMC278 were insomnia
(7.9% versus 7.6% on control), abnormal dreams (6.7% versus 9.7% on control) and
depression (5.8% versus 4.7% on control).
Abnormal dreams/nightmare (a planned psychiatric event of interest grouped term,
“abnormal dreams/nightmare”, see Section 2.5.5.2.3.2.1) were reported at a statistically
significantly lower incidence in the TMC278 group (8.7%) than in the control group (13.2%)
(p = 0.0093; Fisher exact test). Although abnormal dreams/nightmares were also seen at a
lower incidence for the TMC278 group in each of the individual trials, the difference
between treatment groups was not statistically significant for the trials individually. Anxiety
was also seen at a lower incidence on TMC278 than on control (2.3% versus 5.1%).
Psychiatric events of interest were reported in a greater proportion of subjects with a history
of psychiatric illness than in subjects without a history of psychiatric illness, both for
TMC278 (34.5% versus 21.1%) and control (41.0% versus 26.0%).
In conclusion, TMC278 appeared to have limited potential for inducing psychiatric events,
and this was numerically lower than in the control group.
2.5.5.8.3.
Tenofovir DF
Psychiatric effects are not considered to be a safety concern for TDF.
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2.5.5.8.4.
Final
The proposed FTC/RPV/TDF prescribing information describes the following adverse
reactions as “common”:
x
Depression, insomnia, abnormal dreams, sleep disorders
And as “uncommon”:
x
Depressed mood
2.5.5.9.
Hepatic Events
2.5.5.9.1.
Emtricitabine
Hyperbilirubinemia and transaminase elevations (AST and/or ALT) have been identified as
adverse reactions to FTC in clinical trials. Hepatic effects are not considered to be an
important safety concern for FTC other than risks of posttreatment hepatic flares in
HIV/HBV coinfected patients (Section 2.5.5.12.5).
2.5.5.9.2.
Rilpivirine
Hepatic AEs were of special interest because in certain cases ARV treatments have been
associated with hepatotoxicity. Safety and toxicity assessments in the clinical trials with
TMC278 included detailed monitoring and management guidelines for hepatic events. For
the Phase 3 pooled analysis and the Phase 2b analysis, based on the list of preferred terms
occurring across all trials, a list of events to be considered as hepatic events of interest was
created including selected preferred terms from 3 SOCs: hepatobiliary disorders,
investigations, and infections and infestations. The list of preferred terms considered as
hepatic events of interest is presented in Module 2.7.4, Appendix 2.7.4.7.3, Section 1.3.2.4.1.
In the pooled Phase 3 analysis, the incidence of hepatic events of interest was low and similar
in the TMC278 group (5.5%) and in the control group (6.6%).
There were few reports of Grade 4 hepatic events of interest: 3 subjects had a Grade 4 event
during treatment with TMC278 (nonserious ALT and AST increases, and hepatitis C
infection), versus 6 subjects in the control group. Grade 3 hepatic events of interest were
reported for 1.7% and 3.5% of subjects in the TMC278 and control groups, respectively.
In addition to the above mentioned Grade 3 and 4 events, 3 additional hepatic events were
reported as SAEs (Grade 1 or 2 cholelithiasis in the TMC278 group and Grade 2 AST
increase in the control group).
There were no relevant differences between treatment groups with regard to hepatic SAEs,
whereas there tended to be less hepatic AEs leading to permanent discontinuation with
TMC278 (3 subjects [0.4%] versus 9 subjects [1.3%] in the control group).
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In conclusion, the clinical data have not demonstrated a relevant effect of TMC278 on
hepatic parameters.
Hepatic Impairment
TMC278 is primarily metabolized and eliminated by the liver. A trial to evaluate the
potential impact of mild to moderate hepatic impairment (Child-Pugh class A or B) on the
clinical pharmacokinetics and short-term safety and tolerability of TMC278 has been
conducted in non-HIV infected subjects (C130). Hepatic impairment did not affect the safety
and tolerability profile of TMC278. It was concluded that no dose adjustment is required in
patients with mild to moderate hepatic impairment. The pharmacokinetics of TMC278 have
not been studied in patients with severe hepatic impairment (Child-Pugh class C).
2.5.5.9.3.
Tenofovir DF
Hepatic steatosis, hepatitis and increased liver enzymes (most commonly AST, ALT, gamma
GT) have been identified as adverse drug reactions to TDF from postmarketing experience.
However, hepatic effects are not considered to be an important safety concern for TDF other
than risks of posttreatment hepatic flares in HIV/HBV coinfected patients
(Section 2.5.5.12.5) and hepatic steatosis (mitochondrial toxicity; Section 2.5.5.6).
2.5.5.9.4.
x
Hepatic impairment: Patients with mild to moderate liver disease (Child Pugh Turcotte
(CPT), Grade A and B) may be treated with the normal recommended dose of
FTC/RPV/TDF FDC tablets. As FTC/RPV/TDF has not been studied in patients with
severe hepatic impairment (CPT Grade C), no dosing recommendation can be made for
patients in this subgroup
x
The safety and efficacy of FTC/RPV/TDF have not been established in patients with
significant underlying liver disorders. The pharmacokinetics of FTC have not been
studied in patients with hepatic impairment. Emtricitabine is not significantly
metabolized by liver enzymes, so the impact of liver impairment should be limited. No
dose adjustment is required for RPV in patients with mild or moderate hepatic
impairment (CPT Grade A or B). Rilpivirine has not been studied in patients with severe
hepatic impairment (CPT Grade C). The pharmacokinetics of TFV have been studied in
patients with hepatic impairment and no dose adjustment is required in these patients. It
is unlikely that a dose adjustment would be required for FTC/RPV/TDF in patients with
mild to moderate hepatic impairment.
x
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an
increased frequency of liver function abnormalities during combination antiretroviral
therapy and should be monitored according to standard practice. If there is evidence of
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Final
worsening liver disease in such patients, interruption or discontinuation of treatment must
be considered.
In addition, in the “Pharmacokinetic properties” section of the prescribing information, the
following pharmacokinetic information is provided:
x
Hepatic impairment: The pharmacokinetics of FTC/RPV/TDF FDC have not been
studied in patients with hepatic impairment. It is unlikely that a dose adjustment would be
required for FTC/RPV/TDF in patients with mild to moderate hepatic impairment.
x
The pharmacokinetics of FTC have not been studied in non-HBV infected subjects with
varying degrees of hepatic insufficiency. In general, FTC pharmacokinetics in
HBV-infected subjects were similar to those in healthy subjects and in HIV-infected
subjects.
x
Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing
8 patients with mild hepatic impairment (CPT Grade A) to 8 matched controls and
8 patients with moderate hepatic impairment (CPT Grade B) to 8 matched controls, the
multiple dose exposure of RPV was 47% higher in patients with mild hepatic impairment
and 5% higher in patients with moderate hepatic impairment. Rilpivirine has not been
studied in patients with severe hepatic impairment (CPT Grade C).
x
A single 245-mg dose of TDF was administered to non-HIV infected patients with
varying degrees of hepatic impairment defined according to the CPT classification.
Tenofovir pharmacokinetics were not substantially altered in subjects with hepatic
impairment suggesting that no dose adjustment is required in these subjects. The mean
(%CV) TFV Cmax and AUC0- values were 223 (34.8%) ng/mL and 2,050 (50.8%)
ng•h/mL, respectively, in normal subjects compared with 289 (46.0%) ng/mL and 2,310
(43.5%) ng•h/ml in subjects with moderate hepatic impairment, and 305 (24.8%) ng/mL
and 2,740 (44.0%) ng•h/ml in subjects with severe hepatic impairment.
In the “Undesirable Effects” section of the SmPC the following hepatobiliary events are
included as “common”:
x
Increased transaminases, hyperbilirubinemia
And as “uncommon”:
x
Increased bilirubin
2.5.5.9.5.
Hepatitis B and/or C Coinfection
Safety in hepatic impairment and in subjects with HIV and HBV and/or HCV coinfection,
including hepatitis flare following discontinuation of FTC and TDF, is described in
Section 2.5.5.12.5.
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2.5.5.9.5.1.
Final
Rilpivirine
In order to collect safety data in HIV-1 infected subjects coinfected with hepatitis B and/or C
virus, it was decided to allow recruitment of these subjects in the Phase 2b trial and Phase 3
trials.
In the pooled Phase 3 analysis, approximately 9% of subjects were reported to be coinfected
with hepatitis B and/or C. A similar proportion of subjects were coinfected in each treatment
group. Comparisons between the subgroups must be treated with caution due to the small
number of subjects with hepatitis B and/or C coinfection relative to the number of subjects
without coinfection.
The incidence of hepatic events of interest was similar between treatment groups irrespective
of coinfection status. A higher proportion of TMC278-treated subjects with hepatitis B
and/or C coinfection experienced hepatic events of interest (27.8%) than subjects without
coinfection (3.6%). These events were mostly abnormalities in AST and ALT reported in the
SOC of investigations. Similar results were observed in the control group. The higher rate of
hepatic related events in the hepatitis B/C population is to be expected given their underlying
liver pathology.
Differences in graded laboratory abnormalities between coinfected and not coinfected
subjects were consistent with the underlying chronic hepatitis coinfection. Review of Grade 2
to 4 hepatic laboratory abnormalities for TMC278-treated subjects indicates that Grade 2 to 4
increases in AST and ALT are seen at higher incidence in subjects with hepatitis B and/or C
coinfection (20.4% and 33.3%, respectively) than in subjects who are not coinfected (3.5%
and 2.7%, respectively). On control, AST and ALT increases were seen for 18.2% and 28.8%
of coinfected subjects and for 8.0% and 7.8% of non coinfected subjects.
2.5.5.9.5.2.
x
Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an
increased risk for severe and potentially fatal hepatic adverse reactions. Physicians should
refer to current HIV treatment guidelines for the optimal management of HIV infection in
patients coinfected with hepatitis B virus (HBV). In case of concomitant antiviral therapy
for hepatitis B or C, please refer also to the relevant prescribing information for these
medicinal products. The safety and efficacy of FTC/RPV/TDF FDC tablets have not been
established for the treatment of chronic HBV infection. Emtricitabine and TFV
individually and in combination have shown activity against HBV in pharmacodynamic
studies. Limited clinical experience suggests that FTC and TDF have anti-HBV activity
when used in antiretroviral combination therapy to control HIV infection.
x
Discontinuation of FTC/RPV/TDF FDC tablets therapy in patients coinfected with HIV
and HBV may be associated with severe acute exacerbations of hepatitis. Patients
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Final
coinfected with HIV and HBV who discontinue FTC/RPV/TDF FDC tablets should be
closely monitored with both clinical and laboratory follow-up for at least several months
after stopping treatment. If appropriate, resumption of hepatitis B therapy may be
warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation
is not recommended since posttreatment exacerbation of hepatitis may lead to hepatic
decompensation.
In the “Undesirable effects” section of the prescribing information, the following text is
included:
x
HIV/HBV or HCV coinfected patients: The adverse reaction profile of FTC, RPV, and
TDF in patients coinfected with HIV/HBV or HIV/HCV was similar to that observed in
patients infected with HIV without coinfection. However, as would be expected in this
patient population, elevations in AST and ALT occurred more frequently than in the
general HIV-infected population.
2.5.5.10.
Events of Interest Potentially Related to QT Interval Prolongation
2.5.5.10.1.
Emtricitabine
QT effects are not considered to be a safety concern for FTC.
2.5.5.10.2.
Rilpivirine
In a TQT trial, a QT interval prolongation effect of TMC278 was observed in healthy
volunteers at doses that are multiples (3 to 12 times higher) of the 25 mg once daily dose
selected for further development (see Module 2.7.4, Appendix 2.7.4.7.3, Section 6.1.5.3.1).
Therefore, AEs that could be related to cardiac conduction abnormalities or to rate and
rhythm disturbances were closely monitored in the Phase 3 and Phase 2b trials with
TMC278. A list of events that could potentially be related to QT interval prolongation and
that originates from a “Standardised MedDRA Query” named “Torsade de Pointes/QT
prolongation” was used to identify such events (refer to Module 2.7.4, Appendix 2.7.4.7.3,
Section 1.3.2.4.1 for details).
An independent cardiologist made an integrated assessment of the QT parameters of the
nonclinical and clinical trials to investigate the potential of TMC278 to influence cardiac
repolarization. From the overall review, including data from thorough QT trials,
pharmacokinetic/pharmacodynamic modeling and data from 3 Phase 2/3 trials, it was
concluded that TMC278 at a daily dose of 25 mg is not associated with QTcF interval
prolongation or any proarrhythmic potential. This assessment is included as a “White Paper”
in Module 5.4, TMC278-20100613-Expert-TQT.
The analysis of events of interest potentially related to QTc interval prolongation in the
Phase 3 trials showed that such events were reported at a very low incidence in the pooled
TMC278 group (0.4% of subjects) and in the control group (1.2%). Also, events of interest
potentially related to QTc interval prolongation did not occur more notably at any particular
time period throughout the treatment period in the Week 48 analysis.
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2.5.5.10.2.1.
Final
QTc Interval Over Time
Results of ECG monitoring in the pooled Phase 3 analysis, showed that there was a gradual
increase over time in QTcF interval, which was somewhat higher in the control group
(Figure 11).
Overall, no difference in increase in mean QTcF interval over time was observed in the
subanalysis by gender (Figure 11).
Figure 11.
from Baseline in QTcF interval Over Time: Overall (top) and
Subanalysis by Gender (Phase 3 Week 48 Pooled Analysis)
Women
Men
Source: Module 2.7.4.4.2.1.1, Figure 26 and Figure 27
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Subanalysis by background regimen showed that in each of the background regimen
subgroups, the QTcF interval increase over time was similar in the 2 treatment groups. The
increase in QTcF interval was more pronounced in subjects treated with AZT/3TC compared
with those treated with FTC/TDF, regardless of treatment group (TMC278 or control). The
ABC/3TC subgroup (5.0% of the overall population) was too small to make any meaningful
comparisons between this and the other subgroups.
There were no clinically relevant differences between the TMC278 and control groups in the
incidence of treatment-emergent QTcF abnormalities. During treatment, 0.3% of subjects in
the TMC278 group and 0.2% of subjects in the control group had a prolonged QTcF interval
(> 480 ms) at least once. There were no incidences of a QTcF interval > 500 ms, a typical
proarrhythmic threshold, in either treatment group.
Looking at the incidence of QTc abnormalities over time, abnormalities mostly occurred at
1 or 2 time points in the course of the treatment period, and returned to normal with
continued treatment.
Analysis by concomitant medication with potential impact on the QT interval indicated that
in both treatment groups the mean maximum change from baseline was similar in the
subjects taking CYP3A4 inhibitors and in the subgroup of subjects without QTc
interval-prolonging comedication. The number of subjects taking a potassium-depleting
diuretic or another drug with known QT-prolonging effect was too small to draw valid
conclusions.
2.5.5.10.2.2.
Individual QTcF abnormalities
Abnormal increases from baseline between 30 and 60 ms in QTcF interval were reported in
18.6% of subjects in the TMC278 group and in 19.9% of subjects in the control group. An
increase in QTcF interval greater than 60 ms was recorded in 1.2% of subjects in the
TMC278 group and in 0.9% of subjects in the control group. The abnormal QTcF interval
changes (t 30 ms) resulted in a QTcF interval > 450 ms in 0.9% of subjects in the TMC278
group and in 1.7% of subjects in the control group.
The incidence of ECG abnormalities was similar in the subanalyses by gender, by race, and
in the subanalysis of race by gender. The incidence of an abnormal QTcF interval (> 480 ms)
and the incidence of abnormal changes in QTcF interval were similar for men and women,
both on TMC278 and on control.
The incidence of QTcF interval abnormalities and abnormal changes from baseline was
higher in the subgroup taking AZT/3TC than in the TDF-FTC subgroup, both in the TMC278
group and in the control group.
In conclusion, there were no signs or abnormalities related to QT interval prolongation to
suggest safety issues with the use of TMC278 25 mg once daily in combination with
FTC/TDF, AZT/3TC, or ABC/3TC.
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2.5.5.10.3.
Final
Tenofovir DF
QT effects are not considered to be a safety concern for TDF.
2.5.5.10.4.
The proposed FTC/RPV/TDF prescribing information describes the following in the
interaction section:
x
FTC/RPV/TDF FDC should be used with caution when coadministered with a medicinal
product with a known risk of Torsade de Pointes. There is limited information available
on the potential for a pharmacodynamic interaction between RPV and medicinal products
that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects,
supratherapeutic doses of RPV (75 mg once daily and 300 mg once daily) have been
shown to prolong the QTc interval of the electrocardiogram.
2.5.5.11.
Endocrine Events
2.5.5.11.1.
Emtricitabine
Endocrine effects are not considered to be a safety concern for FTC.
2.5.5.11.2.
Rilpivirine
Endocrine monitoring, including gonadal, adrenal and thyroid, was included as a way of
assessing adrenal and thyroid function, because effects on the adrenal gland were observed in
rats, dogs and cynomolgus monkeys with TMC278 (see Module 2.4). Thyroid monitoring
was not done in Phase 3 trials as close monitoring of thyroid hormone levels in the Phase 2b
trial did not identify any clinically relevant effects of TMC278 on thyroid function.
Additional safety assessments of adrenal function in clinical trials comprised ACTH
stimulation testing, with measurements of basal and stimulated cortisol, 17-OH progesterone,
and aldosterone (the latter only in Phase 3 trials). Basal DHEAS, progesterone,
androstenedione, testosterone and LH were measured in Phase 3 and 2b studies. For the
Phase 3 pooled analysis and the Phase 2b analysis, a list was created of events to be
considered as endocrine events of interest that could be related to adrenal insufficiency
(21-hydroxylase inhibition) and decreased androgen production (17-hydroxylase inhibition).
Preferred terms were selected in the SOCs endocrine disorders, investigations, reproductive
system and breast disorders, cardiac disorders (only preferred term ‘postural orthostatic
tachycardia syndrome’), and skin and subcutaneous tissue disorders.
The incidence of endocrine events of interest in the Phase 3 trials was low in both treatment
groups (5.0% in the TMC278 group and 3.8% in the control group). The incidence of
endocrine events of interest was highest in the first 4 weeks of the study in both treatment
groups.
Adrenal safety is discussed in Section 2.5.5.2.3.2.6.
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The clinical data show that the endocrine effects seen in preclinical studies are not of clinical
relevance and it can be concluded that TMC278 has no clinically relevant effect on endocrine
function in humans.
2.5.5.11.3.
Tenofovir DF
Endocrine effects are not considered to be a safety concern for TDF.
2.5.5.11.4.
Endocrine effects are not considered to be a safety concern for the FTC/RPV/TDF FDC
tablet.
2.5.5.12.
Safety in Special Populations
2.5.5.12.1.
Safety in Pregnancy
Safety in pregnancy and lactation is described in Module 2.7.4.5.5.
2.5.5.12.1.1.
Animal reproduction studies of both FTC and TDF did not indicate harmful effects of either
agent with respect to fertility, pregnancy, fetal development, parturition, or postnatal
development. Postmarketing reports of pregnancy involving exposure to FTC or TDF are
reported to the Antiretroviral Pregnancy Registry. No new safety issues relating to use in
pregnancy have been identified to date; however, the available data are insufficient to
conclude that these drugs are safe to use during pregnancy. Clinical trial and spontaneous AE
data are also being monitored for evidence of mitochondrial disease in children exposed in
utero. Additionally, a cross-sectional study of HIV negative children exposed in utero or
perinatally to NRTIs or NtRTIs is being conducted by the Collaborative Committee for
Mitochondrial Toxicity in Children (MITOC; established by Bristol-Myers Squibb, Gilead,
and GlaxoSmithKline after discussion with the European Medicines Agency [EMEA] and
the Committee for Medicinal Products for Human Use [CHMP]). The primary objective of
the study will be to determine the prevalence of neurological clinical symptoms of severe
cognitive deficiency or motor delay (with or without seizures), suggestive of mitochondrial
dysfunction. Emtricitabine and TDF should be used during pregnancy only when the
potential benefit outweighs the potential risk to the fetus.
2.5.5.12.1.2.
Rilpivirine
Data from nonclinical trials have shown that fertility, early embryonic development, pre- and
postnatal development were not affected by TMC278. Phase 1 drug-drug interaction trials
showed there is no pharmacokinetic interaction between TMC278 and
ethinylestradiol/norethindrone-based oral contraceptives. The gender subgroup analysis of
the Phase 3 safety data indicated that there were no gender-specific safety signals for women.
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TMC278 may therefore represent a good therapeutic option for women of childbearing
potential.
Studies in animals have shown no evidence of embryonic or foetal toxicity or an effect on
reproductive function. The exposures in the rat and rabbit studies that did not show
teratogenicity or effects or embryonic development are respectively 63 times and 97 times
higher than the exposure in patients treated with TMC278 at the recommended human dose
of 25 mg/day. Since there are no adequate and well-controlled or pharmacokinetic studies
with TMC278 in pregnant women, the targeted product information will recommend that
TMC278 should be used during pregnancy only if the potential benefit justifies the potential
risk and that mothers should be instructed not to breastfeed if they are receiving TMC278.
In the 2 Phase 3 trials C209 and C215, 3 pregnancies were reported during treatment with
TMC278 after drug exposure ranging from 59 days to approximately 10 months. All
3 subjects subsequently discontinued the trial. Two of the 3 pregnancies were ongoing at the
time of reporting. One subject gave birth prematurely by caesarean section as there were no
contractions. The baby was born healthy, with no reported anomalies.
2.5.5.12.1.3.
No adequate and well-controlled studies of the Truvada tablet or the FTC/RPV/TDF FDC
tablet have been conducted in pregnant women. Applicable warnings are included in the
proposed FTC/RPV/TDF FDC prescribing information with regard to women of child
bearing potential and pregnancy (see Section 2.5.6).
2.5.5.12.2.
Safety in Elderly Patients
Safety in elderly patients is described in Module 2.7.4.5.1.1.
Clinical studies of FTC or TDF did not include sufficient numbers of elderly subjects
(i.e., aged t 65 years) to allow evaluation of efficacy and safety in this population. Similarly,
the pharmacokinetics of FTC and TDF have not been evaluated in patients t 65 years.
There are limited data from clinical trials on safety and tolerability in adults above 65 years
old. No conclusions can be drawn in the elderly population (i.e., those aged 65 years or over)
since only 2 elderly subjects were treated with TMC278 in the Phase 3 trials. Data are
available from 30 subjects aged 55 years or over who were treated with TMC278 in the
pooled Phase 3 trials. For both the TMC278 and control groups, the type and incidence of
AEs were generally similar in subjects aged t 55 years, compared with subjects aged
< 55 years.
Since elderly patients are more likely to have decreased renal function, the FTC/RPV/TDF
FDC tablet should be used with caution when treating patients over the age of 65 years.
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Final
Safety in Children
Safety in children is described in Module 2.7.4.5.1.1.
Dosing recommendations for FTC in the pediatric setting are provided in the Emtriva SmPC.
The efficacy and safety of TDF as a single drug product in HIV-1 infected children is under
investigation.
The safety profile of TMC278 in children and adolescents is under investigation. TMC278
25 mg once daily will be administered in HIV-1 infected ARV treatment-naive adolescents
aged 12-18 years old in planned pediatric trial C213. A trial in HIV-infected treatment-naive
children < 12 years of age is also planned.
The FTC/RPV/TDF FDC tablet is not recommended for use in children or adolescents
(< 18 years) due to insufficient efficacy and safety data in this population, and the inability to
adjust dose or dose interval, however a Paediatric Investigation Plan has been agreed with the
EMA Paediatric Development Committee (EMEA-000774-PIP01-09, the EMA Opinion is
located in MAA Module 1.10).
2.5.5.12.4.
Safety in Renal Impairment
Safety in renal impairment patients is described in Module 2.7.4.5.1.2.
Data pertinent to renal safety are reviewed in Section 2.5.5.3.
No data are currently available for TMC278 in patients with renal impairment. Since the
renal clearance of TMC278 is negligible (< 1% of total), a decrease in total body clearance is
not expected in patients with renal impairment. For TMC278, no dose adjustment is required
for renally impaired subjects.
Long-term safety data from controlled clinical trials do not demonstrate a causal association
between renal events and TDF therapy. However, postmarketing safety data indicate that
TDF therapy may cause renal adverse reactions. The risk of such events may be increased in
patients with underlying renal impairment. Therefore, the proposed FTC/RPV/TDF FDC
prescribing information is as follows:
Because TFV and FTC are excreted via the kidneys, and exposure is increased in patients
with renal impairment (see Section 2.5.3.3.3), FTC/RPV/TDF FDC tablets are not
recommended for patients with moderate or severe renal impairment (creatine clearance
< 50 mL/min). Patients with moderate or severe renal impairment require dose interval
adjustment of FTC and TDF that cannot be achieved with the combination tablet. Use of
FTC/RPV/TDF FDC tablets should be avoided with concurrent or recent use of a
nephrotoxic medicine. If concomitant use of the FTC/RPV/TDF FDC tablet and nephrotoxic
agents is unavoidable, renal function must be monitored weekly.
Renal failure, renal impairment, elevated creatinine, hypophosphatemia, and proximal
tubulopathy (including Fanconi syndrome) have been reported with the use of TDF in
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clinical practice. It is recommended that creatinine clearance is calculated in all patients prior
to initiating therapy with FTC/RPV/TDF FDC tablets and renal function (creatinine
clearance and serum phosphate) is also monitored every 4 weeks during the first year and
then every 3 months. In patients at risk for renal impairment, including patients who have
previously experienced renal events while receiving adefovir dipivoxil, consideration should
be given to more frequent monitoring of renal function.
If serum phosphate is < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance is decreased to
< 50 mL/min in any patient receiving FTC/RPV/TDF FDC tablets, renal function should be
re-evaluated within one week, including measurements of blood glucose, blood potassium
and urine glucose concentrations. Since FTC/RPV/TDF FDC tablet is a combination product
and the dosing interval of the individual components cannot be altered, treatment with
FTC/RPV/TDF FDC tablets must be interrupted in patients with confirmed creatinine
clearance decreased to < 50 mL/min or decreases in serum phosphate to < 1.0 mg/dL
(0.32 mmol/L). Where discontinuation of therapy with one of the components of
FTC/RPV/TDF FDC tablets is indicated or where dose modification is necessary, separate
preparations of FTC, RPV, and TDF are available.
In the “Undesirable effects” section of the prescribing information the following information
is given:
x
In patients receiving TDF, rare events of renal impairment, renal failure and proximal
renal tubulopathy (including Fanconi Syndrome) sometimes leading to bone
abnormalities (infrequently contributing to fractures) have been reported. Monitoring of
renal function is recommended for patients receiving FTC/RPV/TDF FDC tablets (see
Section 2.5.6).
2.5.5.12.5.
Safety in Hepatic Impairment and in Subjects with HIV and HBV and/or
HCV Coinfection
Safety in hepatic impairment is described in Module 2.7.4.5.1.3.
The pharmacokinetics of TDF were not significantly altered in subjects with hepatic
impairment (see Section 2.5.3.3.4). The pharmacokinetics of FTC have not been established
in patients with hepatic impairment. Emtricitabine is not significantly metabolized by liver
enzymes, and so the impact of liver impairment should be limited for this agent.
Through 144 weeks of treatment in Study GS-01-934, elevations of aspartate
aminotransferase and alanine aminotransferase to > 5 times the upper limit of the normal
range were reported in 3% and 2% of subjects in the FTC + TDF group and 3% and 3% of
subjects in the Combivir group, respectively.
The safety and tolerability profile of TMC278 were not altered in HIV-negative subjects with
mild or moderate hepatic impairment compared to matched healthy control subjects. The
changes in pharmacokinetic parameters in subjects with mild or moderate hepatic impairment
are not considered to be of clinical relevance or cause safety concerns. The prescribing
information for FTC/RPV/TDF FDC tablets for patients with liver disease is as follows:
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The safety and efficacy of FTC/RPV/TDF FDC tablets have not been established in patients
with significant underlying liver disorders. The pharmacokinetics of FTC have not been
studied in patients with hepatic impairment. Emtricitabine is not significantly metabolized by
liver enzymes, so the impact of liver impairment should be limited. No dose adjustment is
required for RPV in patients with mild or moderate hepatic impairment (CPT Grade A or B).
RPV has not been studied in patients with severe hepatic impairment (CPT Grade C). The
pharmacokinetics of TFV has been studied in patients with hepatic impairment and no dose
adjustment is required in these patients. It is unlikely that a dose adjustment would be
required for FTC/RPV/TDF FDC tablets in patients with mild to moderate hepatic
impairment.
Consistent with the underlying chronic hepatitis coinfection, hepatic events of interest and
elevated hepatic parameters were observed at a higher incidence in subjects who were
coinfected with hepatitis B and/or C than in subjects who were not coinfected, and this was
seen in both treatment groups (see Section 2.5.5.9.2). The incidence of hepatic events of
interest in coinfected subjects was comparable in both the TMC278 and control groups. In
the TMC278 group, Grade 2-4 increases in AST and ALT are seen at a higher incidence in
subjects with hepatitis B and/or C coinfection (20.4% and 33.4%, respectively) than in
subjects who are not coinfected (3.5% and 2.7%, respectively).
FTC/TDF tablets are not indicated for the treatment of chronic HBV infection, and safety and
efficacy have not been established in patients coinfected with HBV and HIV-1. A limited
number of HIV-1 infected subjects in clinical trials of TDF and FTC were also coinfected
with HBV, HCV, or both.
Since TDF and FTC demonstrate anti-HBV activity, there is a potential risk of hepatitis flare
following discontinuation of these agents, not unlike that observed with other agents with
anti-HBV activity (e.g., adefovir dipivoxil and 3TC). Although the postmarketing data are
limited, hepatitis flares, or possible signs and symptoms of hepatitis flares, have been
observed following withdrawal of treatment with FTC/TDF in subjects coinfected with
HIV-1 and HBV. Warnings and guidance in relation to use of the FTC/RPV/TDF FDC tablet
this population are as follows:
Discontinuation of FTC/RPV/TDF FDC therapy in patients coinfected with HIV and HBV
may be associated with severe acute exacerbations of hepatitis. Patients coinfected with HIV
and HBV who discontinue FTC/RPV/TDF FDC tablet should be closely monitored with both
clinical and laboratory follow-up for at least several months after stopping treatment. If
appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced
liver disease or cirrhosis, discontinuation of anti-HBV therapy is not recommended since
posttreatment exacerbation of hepatitis may lead to hepatic decompensation.
2.5.5.13.
Conclusions on Safety Experience
Emtricitabine and TDF were each evaluated for safety in substantial populations of clinical
study subjects treated with the individual agents in various combinations with other licensed
antiretroviral agents. Data from controlled clinical studies of combination regimens including
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FTC + TDF demonstrated acceptable tolerability and safety profiles to support use in the
adult HIV-1 infected population.
The safety and tolerability profile of TMC278 for the treatment of HIV-1 infection in ARV
treatment-naive adult patients is supported by a safety database derived from 35 trials, which
is robust in terms of numbers of subjects receiving the recommended dose and formulation
and the length of treatment.
In the Phase 3 trials, the most common AEs (> 10% of subjects) with TMC278 were
headache (13.8%), nausea (13.4%), diarrhea (11.4%) and nasopharyngitis (10.1%), reported
at a similar incidence in the control group. Dizziness (28.4%) and rash (13.2%) were
common in the control group, and reported at a significantly higher rate than with TMC278.
In the TMC278 group, the most frequently reported AEs (> 5% of subjects) that were
reported to be at least possibly related to treatment by the investigator were nausea (10.1%
versus 11.3% on control), dizziness (8.0% versus 26.2% on control), abnormal dreams (6.3%
versus 9.4% on control) and headache (6.1% versus 6.2% on control).
The incidence of any treatment-related Grade 2 to 4 AEs was lower in the TMC278 group
(15.9%) than in the control group (31.1%). Incidences of treatment-related rash (individual
preferred term) and dizziness with a severity grade of at least 2 were significantly less
frequent with TMC278 (0.6% each) than with control (5.3% and 6.3%, respectively).
The incidence of any Grade 3 or 4 AE, regardless of relationship to study medication, was
also lower in the TMC278 group (13.3%) than in the control group (18.0%). The most
common Grade 3 or 4 AEs were related to laboratory abnormalities in the SOC of
investigations.
Serious AEs were reported in 6.6% and 8.1% of subjects in the TMC278 and control group,
respectively. There was no consistent pattern of SAEs in either treatment group. There was
1 death in the TMC278 group and 4 deaths in the control group; none was considered to be
related to the study medication.
AEs leading to permanent treatment discontinuation occurred less frequently in the TMC278
group (3.4%) than in the control group (7.6%). TMC278-treated subjects who discontinued
due to AEs did so later than subjects in the control group and this difference was sustained
throughout the treatment period. The incidence of any individual AE leading to
discontinuation was below 0.5% in the TMC278 group.
Special attention was given to the following AEs of interest: skin events, neurologic events,
psychiatric events, hepatic events, endocrine events, and events potentially related to QT
interval prolongation.
Rash (grouped term) was the most common skin event of interest and was reported
significantly less frequently in the TMC278 group (7.4%) than in the control group (22.0%)
(p < 0.001). The incidence of other skin events of interest was low. Consistent with rashes
related to other drugs, most rash events emerged during the first 4 weeks of treatment and
were usually mild to moderate. There were no Grade 4 rashes. Treatment-related Grade 3
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rash was reported in 0.1% of subjects in the TMC278 group and in 0.7% of subjects in the
control group. Treatment-related rash (grouped term) led to permanent treatment
discontinuation of 0.1% of TMC278-treated subjects and of 1.6% subjects in the control
group. The incidence of rash showed no gender difference.
The incidence of neurologic events of interest (mostly Grade 1 or 2) was lower on TMC278
(26.8%) than on control (45.2%). The most commonly reported neurologic events of interest
were headache (13.8% with TMC278, 13.5% with control), dizziness (9.9% versus 28.4%)
and somnolence (4.1% versus 7.5%). Psychiatric events of interest (mostly Grade 1 or 2)
were reported for 23.9% subjects in the TMC278 group compared with 29.0% subjects in the
control group. A significant difference in favor of TMC278 was seen for combined
individual preferred terms abnormal dreams/nightmare.
In the other categories of AEs of interest, i.e., hepatic events, endocrine events, and events
potentially related to QT interval prolongation, the incidence and severity of events was low
and similar in both treatment groups.
With respect to laboratory safety, changes from baseline in hemoglobin by background
regimen showed a transient mean hemoglobin decrease in the AZT/3TC subgroup consistent
with the known hematotoxic effect of AZT.
A mean increase in serum creatinine and consequently a decrease in eGFRcreat were seen at
the first on-treatment assessment in the TMC278 treatment group, but these remained stable
over time. In line with the known effect of TDF, these changes were more pronounced in the
FTC/TDF subgroup. There were no treatment discontinuations due to renal impairment or
elevated serum creatinine. Estimating GFR with the more appropriate marker of cystatin C,
there was an increase in eGFRcyst at Week 2 and at Week 24 in both treatment groups,
indicating that there is no TMC278-induced nephrotoxicity.
Mean total and LDL cholesterol values over time remained close to baseline in TMC278
group, while mean values for these lipids increased significantly in the control group. The
increase in HDL cholesterol over time was less pronounced with TMC278 than with control
subjects, and there was no difference between treatment groups at Week 48 in decrease from
baseline of the total cholesterol/HDL ratio. Mean triglyceride values remained close to
baseline throughout the trial in both treatment groups, showing a small decrease with
TMC278 and a small increase with control. Changes over time in the hepatic, pancreatic and
other laboratory parameters were modest in both treatment groups with no substantial
difference between the treatment groups and none were considered clinically relevant.
The majority of treatment-emergent laboratory abnormalities were Grade 1 or 2 in severity.
The incidence of Grade 3 or 4 laboratory abnormalities was lower with TMC278 (10.9%)
than with control (17.6%). The difference between the treatment groups in the incidence of
Grade 3 or 4 increases was statistically significant in favor of TMC278 for total cholesterol,
LDL cholesterol, and triglycerides. No Grade 4 laboratory abnormalities were reported in
more than 2 subjects (0.3%) in the TMC278 group, with the exception of AST (0.7%) and
ALT (0.4%).
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There were no consistent or clinically relevant changes in vital signs with TMC278. There
was a gradual increase over time in the mean QTcF interval in both treatment groups with no
gender difference. This increase was less pronounced in the FTC/TDF subgroup than in the
AZT/3TC subgroup. The incidence of prolonged QTcF interval (>480 ms) was low with
TMC278 (0.3%) and with control (0.2%). There were no QTcF increases > 500 ms, a typical
proarrhythmic threshold. No AEs suggestive of ventricular tachyarrhythmia were reported.
There was no relationship between exposure to TMC278 (AUC24h) at a dose of 25 mg once
daily and the maximum change from baseline in QTcF interval.
Small variations in adrenal and gonadal parameters indicate that neither TMC278 nor control
had a clinically relevant inhibitory effect on 21-hydroxylase or on 17-hydroxylase. There
were no clinically relevant changes in any of the adrenal safety parameters. There were no
clinical signs or symptoms suggestive of an adrenal or gonadal dysfunction.
Subgroup analyses by background N(t)RTI regimen, gender, race, age, hepatitis B/C
coinfection, Center for Disease Control and Prevention (CDC) category at screening and
CD4+ cell count at baseline did not reveal any notable or unexpected differences between
subgroups. TMC278 was safe and well tolerated with all of the background regimens studied.
Differences between the background regimen subgroups were generally consistent with the
established safety profile of the individual NRTIs used. As would be expected, subjects with
hepatitis B and/or C coinfection had a higher incidence of hepatic events of interest and
elevated hepatic parameters, mostly increases in AST and ALT.
In the Phase 3 analysis, a smaller proportion of subjects in the TMC278 group experienced
an ADR (51.6% on TMC278 versus 67.9% on control) when compared with the control
group. The most common ADRs of at least Grade 2 reported with TMC278 treatment were
depression (3.5%), insomnia (2.9%), headache (2.6%), transaminases increased (2.5%) and
rash (2.2%). The greatest differences between the treatment groups in the incidence of ADRs
of at least Grade 2 were seen for rash (2.2% on TMC278 versus 9.4% on control) and
dizziness (0.7% on TMC278 versus 6.6% on control). Although the incidence was low in
both treatment groups, there was a trend for a higher incidence in the control group of Grade
3 and 4 ADRs (3.1% on TMC278 versus 5.6% on control) and ADRs leading to permanent
discontinuation (1.6% versus 4.0%). There were no additional preferred terms identified as
ADRs from the (pooled) Phase 1, Phase 2a and Phase 2b trials that were not listed for the
pooled Phase 3 ADR analysis.
In conclusion, TMC278 treatment in the Phase 3 trials was generally safe and well tolerated
when administered for up to 48 weeks to HIV-infected, treatment-naive adults at a dose of
25 mg once daily combined with FTC/TDF, AZT/3TC or ABC/3TC. The incidence was
lower with TMC278 than with control for Grade 3 or 4 AEs, AEs leading to permanent
discontinuation, treatment-related AEs, skin events of interest, i.e., rash (grouped term),
neurologic events of interest (particularly dizziness), and Grade 3 or 4 lipid-related
laboratory abnormalities. There were no laboratory, cardiovascular, or endocrine safety
signals with TMC278. The adverse reaction profile of TMC278, based on thorough review of
clinical safety data, reflects the safety and tolerability of the product and offers benefits over
EFV.
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The once-daily regimen of EFV + FTC + TDF in Study GS-01-934 demonstrated a
preferential safety profile compared with the EFV plus Combivir regimen, as evidenced by
the significantly lower rate of study drug discontinuation due to an AE. No new adverse
reactions associated with the regimen of EFV + FTC + TDF were identified from AEs and
laboratory abnormalities during 144 weeks of treatment.
The 144-week safety data for Study GS-99-903 demonstrate an acceptable safety profile for
the regimen of TDF + 3TC + EFV during long-term treatment in HIV-1 infected subjects.
The regimen was well tolerated with no clinically significant renal or bone toxicity and no
evidence of any other significant drug-related toxicity emerging. The results of several key
measures used to assess safety and tolerability indicate that the TDF regimen has a more
favorable safety profile than the d4T regimen. No new safety issues have emerged with
longer-term treatment in Study GS-99-903 (up to 240 weeks).
The main conclusions in relation to specific safety issues are as follows:
x
There was no evidence of renal toxicity during long-term clinical trials of TDF.
Postmarketing safety data indicate that TDF therapy may cause renal adverse reactions.
These reactions include acute renal failure, renal failure, acute tubular necrosis, Fanconi
syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases),
nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and
polyuria. The following adverse reactions may occur as a consequence of proximal renal
tubulopathy: rhabdomyolysis, osteomalacia (manifested as bone pain and infrequently
contributing to fractures), hypokalemia, muscular weakness, myopathy, and
hypophosphatemia. These events are not considered to be causally associated with TDF
therapy in the absence of proximal renal tubulopathy.
x
The risk of renal toxicity associated with TDF is increased in patients with underlying
renal impairment and those taking nephrotoxic agents. FTC/RPV/TDF FDC tablets are
not recommended for patients with moderate and severe renal impairment
(CLcr < 50 mL/min). Patients with moderate or severe renal impairment require dose
interval adjustment of FTC and TDF that cannot be achieved with the combination tablet.
It is recommended that CLcr be calculated in all patients prior to initiating therapy with
FTC/RPV/TDF FDC tablets and that renal function (CLcr and serum phosphate) also be
monitored every 4 weeks during the first year and then every 3 months. In patients at risk
for renal impairment, including patients who have previously experienced renal events
while receiving adefovir dipivoxil, consideration should be given to more frequent
monitoring of renal function.
x
Long-term clinical safety data demonstrate a minimal risk of bone toxicity with
prolonged administration of TDF. The clinical relevance of the changes in surrogate bone
biomarkers and BMD in treatment-naive subjects is not known. Postmarketing safety data
indicate that osteomalacia (manifested as bone pain and infrequently contributing to
fractures) may occur in some patients experiencing TDF-associated proximal renal
tubulopathy.
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x
Clinical trial safety data and postmarketing experience demonstrate a low risk of
mitochondrial toxicity (lactic acidosis, hepatic steatosis, pancreatitis, peripheral
neuropathy, lipodystrophy, and lipid abnormalities) with FTC and TDF.
x
Due to the lack of safety and efficacy information, the FTC/RPV/TDF FDC tablet is not
recommended for use in children ( 18 years). Only limited data are available to assess
safety in the elderly.
x
The safety of the FTC/TDF tablet or the FTC/RPV/TDF FDC tablet has not been
established in patients with HIV/HBV coinfection. Hepatitis flares, or possible signs and
symptoms of hepatitis flares, have been observed following withdrawal of treatment with
FTC/TDF tablet in subjects coinfected with HIV-1 and HBV.
In conclusion, the NRTI/NtRTI backbone of FTC + TDF has demonstrated an acceptable
safety profile in HIV-1 infected patients that compares favorably with the safety profile of
other NRTI backbones, particularly with respect to mitochondrial toxicity. The clinical trial
and postmarketing safety experience for each agent, together with the substantial clinical trial
data from use of these agents in combination, provide adequate assurance regarding the safe
use of these agents in the FTC/RPV/TDF FDC tablet.
The safety database for TMC278 is robust in terms of numbers of subjects receiving the
recommended dose and formulation and in terms of the cumulative exposure to TMC278.
Conclusions regarding the safety profile of TMC278 are made based on the large
double-blind active-controlled data set. No new or unexpected safety signals were observed
with long-term treatment of TMC278 up to 192 weeks.
Safety information on FTC/RPV/TDF FDC is limited. Two Phase 1 bioequivalence studies
showed that the FDC was well tolerated. No additional adverse drug reactions were identified
in an analysis of the safety database for subjects receiving RPV in combination with
FTC/TDF in Trials C209 and C215.
2.5.6.
Benefits and Risks Conclusions
The therapeutic need remains for new antiretroviral therapies with practical and convenient
dosing regimens that combine potent and sustained efficacy with acceptable tolerability and
minimal long-term toxicity. The most significant challenge in achieving successful long-term
treatment is the prevention of drug resistance. Incomplete adherence to treatment regimens is
probably the most important factor contributing to the development of resistance and
treatment failure. The development of fixed-dose combination products is a strategy
employed to simplify regimens and improve adherence to therapy. The FDC of
FTC/RPV/TDF has the potential to combine a next generation NNRTI, having an improved
safety profile, with the standard-of-care, preferred-agent NRTIs FTC and TDF. Therapy with
FTC/RPV/TDF should be initiated by a physician experienced in the management of HIV
infection. The following considerations support the positive benefit:risk profile for the
FTC/RPV/TDF FDC tablet for the treatment of adult HIV-1 infected patients.
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Benefits
Emtricitabine and TDF are potent and selective HIV-1 reverse transcriptase inhibitors, each
of which has been approved individually for use once-daily in combination with other
antiretroviral agents for the treatment of HIV-1 infection. The long-term clinical benefits of
these agents in combination regimens have been demonstrated in both treatment-naive
(including subjects with a high viral load, i.e., ! 100,000 copies/mL) and
treatment-experienced subjects.
Emtricitabine and TDF is a preferred NRTI/NtRTI backbone for initial therapy of HIV-1
infection, as recommended in international treatment guidelines, on the basis of the
significant clinical efficacy and preferential long-term toxicity profile demonstrated in
controlled clinical trials. Clinical effectiveness was demonstrated by statistically significant
and clinically relevant changes in plasma HIV-1 RNA and CD4 cell counts. The degree of
viral load suppression and virologic response rates indicate potent and durable antiviral
efficacy with a low level of resistance development.
With respect to treatment-experienced patients, the clinical data and resistance profiles for
the individual agents provide adequate assurance that the FTC/RPV/TDF FDC tablet
effectively maintains control of plasma HIV-1 RNA levels with appropriate consideration of
the pattern of mutations and treatment history.
FTC and TDF are the only 2 preferred NRTIs listed in the DHHS Guidelines for
nonpregnant, antiretroviral-naive patients {15207}.
In a Phase 2b trial, TMC278 25 mg had similar efficacy as TMC278 75 mg or 150 mg, or
EFV. The durable antiviral effect of TMC278 containing regimens was shown in the results
of the long-term efficacy analyses of the Phase 2b trial, which demonstrated a persistent
long-term decrease from baseline in viral load and an immunological benefit. The vast
majority of subjects with undetectable viral load (< 50 copies/mL) at Week 96 maintained
this level of virologic suppression to at least 192 weeks of treatment. The controlled safety
data up to 192 weeks of treatment from the Phase 2b trial in which many subjects received
doses of TMC278 higher than 25 mg defined the longer-term safety and tolerability profile of
TMC278. Administration of TMC278 for this longer treatment period did not reveal any
additional or unexpected safety issues than were observed within the first 48 weeks of the
study.
Clinical trial data from 2 Phase 3 studies demonstrate that TMC278 dosed at 25 mg once
daily (with a meal) with a background regimen consisting of 2 N(t)RTIs (approximately 80%
was FTC/TDF), demonstrated substantial and sustained efficacy in a manner that was
noninferior to EFV 600 mg once daily with a similar background regimen.
Response rates in the Phase 3 trials were as high as in recent clinical trials {15040}, {15966},
{15968}, {12654} in this population of ARV treatment-naive HIV-1 infected adult patients.
There were a limited number of virologic failures in the Phase 3 trials C209 and C215, with a
difference in proportion of virologic failures between treatment groups (10.5% with TMC278
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and 5.7% with control). Among virologic failures on TMC278, 62.9% developed NNRTI
mutations, 67.7% had N(t)RTI mutations and 50.0% lost susceptibility to TMC278. Among
TMC278-treated patients who develop resistance to TMC278, cross resistance developed
against EFV (87.1%), ETR (90.3%) and NVP (45.2%). Among virologic failures in the
control group, 53.6% had NNRTI RAMs, 32.1% had N(t)RTI RAMs and 42.9% had
phenotypic resistance to EFV. Among the control virologic failures resistant to EFV, none
were cross-resistant to ETR or TMC278 whereas all demonstrated cross-resistance to NVP.
For the FTC/TDF pooled subset, of the 54 subjects with virologic failure and available
phenotypic resistance data, 37 lost susceptibility to FTC, 29 lost susceptibility to RPV, and
2 lost susceptibility to TDF. Among these subjects, 37 were resistant to lamivudine, 28 were
resistant to etravirine, 26 to efavirenz, and 12 to nevirapine. Reduced susceptibility was
observed to abacavir and/or ddI in some cases.
Based on the resistance results, the overall consequences of virologic failure with TMC278,
irrespective of the comparative frequency of such failure, are similar to that of virologic
failure on other first line NNRTI containing regimens. Given the current availability of
treatment options from multiple ARV classes, a variety of active second line ARV treatment
options could generally be constructed for the limited number of patients who might be
expected to virologically fail TMC278 with the extent and type of drug resistance observed
in Phase 2b and Phase 3 clinical trials. Current practice when selecting a subsequent ARV
regimen can be applied, including the use of viral genotyping and drug resistance assessment.
Specifically ETR, the only NNRTI approved for patients with evidence of NNRTI resistance,
would likely not be an option when selecting a second treatment regimen following TMC278
virologic failure (or virologic failure of any other NNRTI). This is consistent with the label
indication for ETR, which recommends not using ETR with only 2 N(t)RTIs in patients who
have virologically failed a previous NNRTI-containing regimen.
The FDC of FTC/RPV/TDF has the potential to combine a next generation NNRTI, having
an improved safety profile compared to EFV, with the standard-of-care, preferred-agent
NRTIs FTC and TDF. This fixed-dose regimen would potentially be the second highly
active, once daily FDC regimen, and will address limitations with the only other fixed-dose
regimen (EFV/FTC/TDF).
The FDC of FTC/RPV/TDF will provide an attractive treatment option to a significant
number of patients who may wish to avoid using EFV-containing regimens such as Atripla.
Patients may wish to avoid EFV-containing regimens due to tolerability concerns, including
CNS adverse reactions, or the reproductive risk potential associated with EFV in women of
childbearing potential. Thus, there remains a need for new combinations of potent agents
exhibiting favorable tolerability, minimal short and long-term toxicity, and convenient dosing
to maximize patient adherence.
Risk
The individual agents of the FTC/RPV/TDF FDC tablet have each demonstrated acceptable
tolerability and long-term safety profiles to support their use in the adult HIV-1 infected
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population. Clinical experience with FTC/TDF and RPV tablets in subjects in C209 and
C215 demonstrated acceptable safety that demonstrated benefits compared to subjects treated
with FTC/TDF and EFV. Adverse reactions reported in clinical trials and postmarketing
experience are included in the proposed FTC/RPV/TDF FDC tablet prescribing information.
The principal warnings or precautions applicable to the individual agents are provided in the
proposed FTC/RPV/TDF FDC tablet prescribing information. The FTC/RPV/TDF FDC
tablet is proposed for treatment of HIV-1 infection in adults and is not recommended for
pediatric patients. No additional warnings or precautions are proposed for use of the
FTC/RPV/TDF FDC tablet. As a fixed-dose combination, the FTC/RPV/TDF FDC tablet
should not be administered with other medicinal products containing the same active
components, or with other cytidine analogues such as 3TC, or with adefovir dipivoxil.
Based on preclinical findings that identified the gastrointestinal tract, the renal tubular
epithelium, and bone as target organs of toxicity associated with TDF treatment, safety
monitoring relevant to these organ systems has been extensively conducted and evaluated
during the clinical development of TDF. Overall, the clinical assessment does not reveal
significant clinical toxicity associated with TDF therapy even with prolonged administration.
Long-term safety data from clinical trials do not demonstrate a causal association between
renal events and TDF therapy. Postmarketing safety data indicate that TDF therapy may
cause renal adverse reactions. These reactions include acute renal failure, renal failure, acute
tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis
(including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased
creatinine, proteinuria, and polyuria. The following adverse reactions may occur as a
consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested as
bone pain and infrequently contributing to fractures), hypokalemia, muscular weakness,
myopathy, and hypophosphatemia. These events are not considered to be causally associated
with TDF therapy in the absence of proximal renal tubulopathy.
Controlled 48-week safety data from the Phase 3 trials demonstrate that TMC278 in an ARV
treatment regimen resulted in a favorable safety and tolerability profile with clinically
relevant tolerability advantages (neurologic, rash and serum lipids) over EFV.
The most common AEs with TMC278 were headache, nausea, diarrhea, and nasopharyngitis,
and these were reported at rates similar to those with EFV. Dizziness, rash and abnormal
dreams/nightmare, which were common in the control group, were reported at a significantly
lower rate with TMC278. Incidences of hepatic events with TMC278 were low and similar to
those with EFV. Grade 3 or 4 laboratory abnormalities in lipids (increases in total
cholesterol, LDL cholesterol and triglycerides) were significantly more common with EFV
than with TMC278.
Importantly, fewer subjects on TMC278 discontinued because of AEs (3.4%) than subjects in
the control group (7.6%). TMC278-treated subjects who discontinued due to AEs did so later
than subjects in the control group and this difference was sustained throughout the treatment
period. The most common AEs leading to discontinuation on TMC278 belonged to the SOC
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psychiatric disorders (1.5% versus 2.2% on control). In the control group, subjects mostly
discontinued due to AEs in the SOCs of skin and subcutaneous tissue disorders (0.3% on
TMC278 versus 1.8% on control), all related to rash, infections and infestations (0.3% on
TMC278 versus 1.3% on control), and psychiatric disorders (1.5% on TMC278 versus 2.2%
on control).
Based on the nonclinical safety studies, adrenal function was carefully monitored in the
clinical trials. However, Phase 3 and Phase 2b trials did not highlight any safety concerns
with respect to adrenal function or endocrine events.
TMC278 has a good safety profile over the dose range tested and the exposures achieved.
TMC278 at the recommended dose of 25 mg once daily is not associated with a clinically
relevant effect on QTc. At supratherapeutic doses of 75 mg and 300 mg once daily in healthy
volunteers, a dose-related prolongation of corrected QT intervals was seen. The clinical
significance of this is unknown. Therefore a warning is included in the prescribing
information that the FTC/RPV/TDF FDC tablet should be used with caution when
coadministered with a medicinal product with a known risk of Torsade de Pointes.
Small mean increases in creatinine and mean decreases in eGFRcreat were seen over time with
TMC278, but not with EFV. There were no treatment discontinuations due to renal
impairment or elevated creatinine. Using creatinine as a marker for eGFR, there was a mean
decrease from baseline in eGFRcreat in the TMC278 group. Estimating GFR with the more
appropriate marker of cystatin C, there was an increase in eGFRcyst at Week 2 and at
Week 24 in both treatment groups, indicating that there is no TMC278-induced
nephrotoxicity. Subjects with renal impairment are not expected to have altered disposition
of TMC278, as renal elimination is a negligible (<1%) route of excretion. No special
precautions or dose adjustments are required in patients with renal impairment.
Subgroup analyses of AEs by age, race and gender did not reveal any clinically meaningful
differences in AE profile. TMC278 was generally safe and well-tolerated after 48 weeks of
treatment.
TMC278 can be used in special populations without increased risk. Hepatitis B and/or C
coinfected subjects can be treated with TMC278 at the recommended dose, with the standard
clinical monitoring for HIV/hepatitis coinfected patients. A clinical trial indicated that the
tolerability profile of TMC278 was not altered in non-HIV infected subjects with mild or
moderate hepatic impairment. TMC278 can be used in patients with mild to moderate hepatic
impairment without dose adjustment. Coadministration of TMC278 in healthy volunteers on
a stable methadone maintenance therapy was generally safe and well tolerated and it did not
have a clinically relevant effect on pharmacodynamic parameters of the treatment of opiate
dependence.
From genetic toxicology studies it was concluded that there was no potential for
carcinogenicity by a direct interaction of TMC278 or its metabolites with DNA, at exposures
up to 21-fold (mice) and 3-fold (rats), relative to those observed in humans at the
recommended dose (25 mg once daily).
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Data from nonclinical trials have shown that fertility, early embryonic development, pre- and
postnatal development were not affected by TMC278. Phase 1 drug-drug interaction trials
showed there is no pharmacokinetic interaction between TMC278 and ethinylestradiol/
norethindrone-based oral contraceptives. The gender subgroup analysis of the Phase 3 safety
data indicated that there were no gender-specific safety signals for women. Unlike efavirenz,
TMC278 may therefore represent a good therapeutic option for women of childbearing
potential. Until more clinical data are generated, TMC278 should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
No clear relationship was observed between TMC278 pharmacokinetics at a dose of
25 mg once daily and the occurrence of AEs of special interest or changes in relevant
laboratory parameters with the TMC278 25 mg once daily dose. There was also no
relationship between exposure to TMC278 and the maximum change from baseline in QTcF
interval, over the exposures achieved with the TMC278 25 mg once daily dose.
The following conditions that are likely to result in decreased TMC278 exposure
(sub-optimal adherence, intake without food, missing doses, coadministration with
exposure-lowering drugs) should be avoided during treatment with TMC278. Drugs that alter
intra-gastric pH may affect the solubility of TMC278, therefore, TMC278 should not be
coadministered with proton pump inhibitors since coadministration may cause significant
decreases in TMC278 plasma concentrations. For drugs with a short-lived effect on
intra-gastric pH, such as the H2-antagonists and antacids, an effect on TMC278 exposure can
be circumvented by separating the intake of the drugs in time. TMC278 should not be taken
with CYP3A inducers as these could decrease TMC278 plasma concentrations, and
potentially reduce the therapeutic effect of TMC278. TMC278 can be used with many other
medications generally used in HIV-1 infected patients.
The risk assessments, based on the currently available clinical and preclinical data, indicate
that continued monitoring of the safety profile during ongoing and planned clinical trials and
routine pharmacovigilance activities provide sufficient tools to manage the potential risks for
TMC278. The long-term data of the Phase 2b trial, which contributed to the understanding of
the safety of TMC278, did not identify any new types of AEs emerging from 192 weeks of
treatment with TMC278. Moreover, TMC278 is an NNRTI, a well-characterized class of
HIV compounds that has had extensive use for over 10 years. Therefore, no additional risk
minimization activities are proposed.
Appropriate guidance is included in the proposed FTC/RPV/TDF FDC tablet prescribing
information to reduce the risk for development of renal events, notably with respect to
patients with pre-existing renal impairment and concomitant use with nephrotoxic agents and
agents that are eliminated by active tubular secretion. It is recommended that CLcr is
calculated in all patients prior to initiating therapy and, as clinically appropriate, during
FTC/RPV/TDF therapy. Routine monitoring of calculated CLcr and serum phosphorus should
be performed in patients at risk for renal impairment, including patients who have previously
experienced renal events while receiving adefovir dipivoxil. Renal toxicity remains under
constant review in the pharmacovigilance setting. FTC/RPV/TDF tablets are not
recommended for patients with moderate or severe renal impairment (CLcr < 50 mL/min).
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Patients with moderate or severe renal impairment require a dose adjustment of FTC and
TDF that cannot be achieved with the combination tablet.
Based on clinical trial data, there appears to be a minimal risk of bone toxicity with
prolonged administration of TDF. Long-term safety evaluations in both
treatment-experienced and treatment-naive subjects have demonstrated no increased risk of
bone fracture. The clinical significance of changes in bone biomarkers or BMD in
treatment-naive subjects is unknown. Postmarketing safety data indicate that osteomalacia
(manifested as bone pain and infrequently contributing to fractures) may occur in some
patients experiencing TDF–associated proximal tubulopathy. Postmarketing bone AEs
remain under close monitoring. The proposed FTC/RPV/TDF FDC tablet prescribing
information indicates that if bone abnormalities are suspected then appropriate consultation
should be obtained.
Emtricitabine and TDF appear to have a low potential for mitochondrial toxicity, as
demonstrated by enzyme and cell analyses in vitro and by markers of mitochondrial injury.
Rilpivirine does not inhibit the mitochondrial DNA polymerase Ȗ. Overall, assessment of
clinical safety data from ongoing clinical studies and during postmarketing experience
continues to demonstrate a low risk of mitochondrial toxicity (lactic acidosis, hepatic
steatosis, pancreatitis, peripheral neuropathy, lipodystrophy, and lipid abnormalities) with
FTC, RPV, and TDF. Nonetheless, nucleoside analog class-related warnings regarding lactic
acidosis and hepatic steatosis are included in the proposed FTC/RPV/TDF FDC tablet
prescribing information.
The safety and efficacy of the FTC/RPV/TDF FDC tablet have not been established in
patients with significant underlying liver disorders. The pharmacokinetics of FTC have not
been studied in patients with hepatic impairment; however, FTC is not significantly
metabolized by liver enzymes, and so the impact of liver impairment should be limited. A
clinical trial indicated that the tolerability profile of TMC278 was not altered in non-HIV
infected subjects with mild or moderate hepatic impairment. TMC278 can be used in patients
with mild to moderate hepatic impairment without dose adjustment (CPT Grade A or B).
TMC278 has not been studied in patients with severe hepatic impairment (CPT Grade C).
The pharmacokinetics of TFV have been studied in patients with hepatic impairment and no
dosage adjustment is required in these patients. It is therefore unlikely that a dose adjustment
would be required for the FTC/RPV/TDF FDC tablet in patients with mild to moderate
hepatic impairment.
The FTC/RPV/TDF FDC tablet is not indicated for the treatment of chronic HBV infection,
and safety and efficacy have not been established in patients coinfected with HBV and
HIV-1. Since TDF and FTC demonstrate anti-HBV activity, there is a potential risk of
hepatitis flare following discontinuation of these agents, not unlike that observed with other
agents with anti-HBV activity (e.g., adefovir dipivoxil and 3TC). No activity of RPV was
observed against HBV at concentrations up to 10 PM. Although the postmarketing data are
limited, hepatitis flares, or possible signs and symptoms of hepatitis flares, have been
observed following withdrawal of treatment with Truvada in patients with HBV. Clinical and
laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of
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Truvada in patients coinfected with HIV-1 and HBV; a warning related to the risk of hepatic
flare following discontinuation of treatment in these patients is provided in the proposed
FTC/RPV/TDF FDC prescribing information.
No adequate and well-controlled studies of the FTC/RPV/TDF FDC tablet or its components
have been conducted in pregnant women. The FTC/RPV/TDF FDC tablet should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Due to the lack of safety and efficacy information, the FTC/RPV/TDF FDC tablet is not
recommended for use in children.
A number of reports of overdose have occurred during postapproval use of FTC and TDF.
The individual component agents of the fixed-dose combination product (i.e., FTC, RPV, or
TDF) or any other combination containing these agents should not be administered
concurrently with the FTC/RPV/TDF FDC tablet. A warning has therefore been included in
the prescribing information advising not to coadminister with other medicinal products
containing the same components as the FTC/RPV/TDF FDC tablet. If overdose occurs, the
patient should be monitored for evidence of toxicity and standard supportive treatment
applied as necessary including observation of the clinical status of the patient and monitoring
of vital signs and ECG (QT interval).
In conclusion, the therapeutic efficacy and acceptable tolerability and safety profiles
established for the individual agents support the clinical utility and acceptable benefit:risk
profile of the FTC/RPV/TDF FDC tablet in HIV-1 infected patients.
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Final
References
Copies of the references cited in this document are provided in Module 5.4.
Dobs A. White Paper on Endocrine Safety Evaluation of TMC278 (rilpivirine). 2010:1-34.
Shah RR. White Paper on QT-prolonging and proarrhythmic potentials of TMC278
(rilpivirine). 2010:1-54.
39
Balzarini J, Holý A, Jindrich J, Naesens L, Snoeck R, Schols D, et al. Differential
antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic
nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus
activities of (R)-9-(2-phosphonomethoxypropyl)-2, 6-diaminopurine. Antimicrob
Agents Chemother 1993;37 (2):332-8.
625
Balzarini J, Aquaro S, Perno CF, Witvrouw M, Holý A, De Clercq E. Activity of
the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and 9-(2phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency
virus in different human cell systems. Biochem Biophys Res Commun 1996;219
(2):337-41.
1003
Gu Z, Gao Q, Fang H, Salomon H, Parniak MA, Goldberg E, et al. Identification
of a mutation of codon 65 in the IKKK motif of reverse transcriptase that encodes
human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'dideoxy-3'-thiacytidine. Antimicrob Agents Chemother 1994;38 (2):275-81.
1004
Zhang D, Caliendo AM, Eron JJ, DeVore KM, Kaplan JC, Hirsch MS, et al.
Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the
human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents
Chemother 1994;38 (2):282-7.
1131
Cherrington JM, Allen SJW, Bischofberger N, Chen MS. Kinetic interaction of the
diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and other anti-HIV active
purine congeners with HIV reverse transcriptase and human DNA polymerases D,
E, and J. Antivir Chem Chemother 1995;6 (4):217-21.
1469
Mulato AS, Cherrington JM. Anti-HIV activity of adefovir (PMEA) and PMPA in
combination with antiretroviral compounds: in vitro analyses. Antiviral Res
1997;36 (2):91-7.
1574
Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human
immunodeficiency virus activity and cellular metabolism of a potential prodrug of
the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine
(PMPA), Bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob Agents Chemother
1998;42 (3):612-7.
CONFIDENTIAL
Page 170
18AUG2010
Final
1649
Miller MD, Anton KE, Mulato AS, Lamy PD, Cherrington JM. Human
immunodeficiency virus type 1 expressing the lamivudine-associated M184V
mutation in reverse transcriptase shows increased susceptibility to adefovir and
decreased replication capability in vitro. J Infect Dis 1999;179 (1):92-100.
1793
Tisdale M, Alnadaf T, Cousens D. Combination of mutations in human
immunodeficiency virus type 1 reverse transcriptase required for resistance to the
carbocyclic nucleoside 1592U89. Antimicrob Agents Chemother 1997;41
(5):1094-8.
1794
Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of human
immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a
mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA
1993;90 (12):5653-6.
2078
Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, et al. In
vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA.
Antivir Ther 1999;4 (2):87-94.
2141
De Antoni A, Foli A, Lisziewicz J, Lori F. Mutations in the pol gene of human
immunodeficiency virus type 1 in infected patients receiving didanosine and
hydroxyurea combination therapy. J Infect Dis 1997;176:899-903.
2226
Fischl MA, Richman DD, Hansen N, Collier AC, Carey JT, Pra MF, et al. The
safety and efficacy of zidovudine (AZT) in the treatment of subjects with midly
symptomatic human immunodeficiency virus type 1 (HIV) infection. A doubleblind, placebo-controlled trial. Ann Intern Med 1990;112 (10):727-37.
2368
Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the
replication of the DNA polymerase M550V mutation variant of human hepatitis B
virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral
Hepat 2000;7 (2):161-5.
2516
Kramata P, Birkus G, Otmar M, Votruba I, Holy A. Structural features of acyclic
nucleotide analogs conferring inhibitory effects on cellular replicative DNA
polymerases. Collection Symposium Series (Holy A and Tocik Z, eds), Institute of
Organic Chemistry and Biochemistry, Academy of Sciences of Czech Republic,
Prague, Czech Republic 1996;1:188-91.
2520
Cihlar T, Ho ES, Lin DC, Mulato AS. Human renal organic anion transporter 1
(hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs.
Nucleosides Nucleotides Nucleic Acids 2001;20 (4-7):641-8.
2522
Brinkman K, Ter Hofstede HJ, Burger DM, Smeitink JAM, Koopmans PP.
Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as
common pathway. AIDS 1998;12 (14):1735-44.
CONFIDENTIAL
Page 171
18AUG2010
Final
2537
Palella FJ, Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et
al. Declining morbidity and mortality among patients with advanced human
immunodeficiency virus infection. N Engl J Med 1998;338 (13):853-60.
3320
Birkus G, Hitchcock MJM, Cihlar T. Assessment of mitochondrial toxicity in
human cells treated with tenofovir: comparison with other nucleoside reverse
transcriptase inhibitors. Antimicrob Agents Chemother 2002;46 (3):716-23.
3467
Cooper D, Coakley DF, Sayre J, Mittan A, Zhong L, Chen S-S, et al. Anti-hepatitis
B virus (HBV) activity of tenofovir disoproxil fumarate (TDF) in lamivudine
(LAM) experienced HIV/HBV co-infected patients [poster]. XIV International
AIDS Conference; 2002 Jul 7-12; Barcelona, Spain. Poster Number 6015.
3940
Nunez M, Perez-Olmeda M, Diaz B, Rios P, Gonzalez-Lahoz J, Soriano V.
Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients
failing or partially responding to lamivudine. AIDS 2002;16 (17):2352-4.
4241
Flint WC. Challenges facing family practice and primary care. JAMA 2003;289
(3):297.
4249
Wilson JE, Martin JL, Borroto-Esoda K, Hopkins S, Painter G, Liotta DC, et al.
The 5'-triphosphates of the (-) and (+) enantiomers of cis-5-fluoro-1-[2(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human
immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents
Chemother 1993;37 (8):1720-2.
4256
Chesney MA. Factors affecting adherence to antiretroviral therapy. Clin Infect Dis
2000;30 (Suppl 2):S171-S6.
4266
Stone VE, Jordan J, Tolson J, Pilon T. Potential impact of once daily regimens on
adherence to HAART [abstract]. 40th Annual Meeting of the Infectious Disease
Society of America; 2002 Oct 24-27; Chicago, Ill. p. 129. Abstract 486.
4343
McColl DJ, Margot NA, Cheng AK, Miller MD. Development of K65R versus
thymidine analogue-associated mutations (TAMs) in antiretroviral-treated patients.
In: Abstracts of the 6th International Congress on Drug Therapy in HIV Infection;
2002 Nov 17-21; Glasgow, UK. Abstract P206.
4376
Bruno R, Sacchi P, Zocchetti C, Ciappina V, Puoti M, Filice G. Rapid hepatitis B
virus-DNA decay in co-infected HIV-hepatitis B virus 'e-minus' patients with
YMDD mutations after 4 weeks of tenofovir therapy. AIDS 2003;17 (5):783-4.
4526
Jeong LS, Schinazi RF, Beach JW, Kim HO, Nampalli S, Shanmuganathan K, et
al. Asymmetric synthesis and biological evaluation of beta-L-(2R,5S)- and alphaL-(2R,5R)-1,3-oxathiolane-pyrimidine and -purine nulceosides as potential antiHIV agents. J Med Chem 1993;36 (2):181-95.
CONFIDENTIAL
Page 172
18AUG2010
Final
4527
Paff MT, Averett DR, Prus KL, Miller WH, Nelson DJ. Intracellular metabolism
of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in
HepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob Agents Chemother
1994;38 (6):1230-8.
4534
Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A, et al.
Selective inhibition of human immunodeficiency viruses by racemates and
enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
Antimicrob Agents Chemother 1992;36 (11):2423-31.
4535
Furman PA, Davis M, Liotta DC, Paff M, Frick LW, Nelson DJ, et al. The antihepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+)
enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
4541
Painter G, St. Clair MH, Chingm S, Noblin J, Wang L, Furman PA. 524W91.
Anti-HIV, Anti-Hepatitis B Virus. Drugs of the Future 1995;20 (8):761-5.
4620
Kaul S, Damle B, Bassi K, Xie J, Gale J, Ryan K, et al. Pharmacokinetic
evaluation of reduced doses of didanosine enteric coated capsules (ddI-EC) in
combination with tenofovir disoproxil fumarate (TDF) and food for a once-daily
antiretroviral regimen [poster]. 4th International Workshop on Clinical
Pharmacology of HIV Therapy; 2003 March 27-29; Cannes, France. Poster 8.1.
4630
Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients
with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med 2003;348
(2):177-8.
5010
Miller MD, Margot N, Lu B, Zhong L, Chen S-S, Cheng A, et al. Genotypic and
phenotypic predictors of the magnitude of response to tenofovir disoproxil
fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004;189
(5):837-46.
5024
Thio CL, Seaberg EC, Skolasky R, Jr, Phair J, Visscher B, Munoz A, et al. HIV-1,
hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort
Study (MACS). Lancet 2002;360 (9349):1921-6.
5044
Palmer S, Margot N, Gilbert H, Shaw N, Buckheit R, Jr, Miller M. Tenofovir,
adefovir, and zidovudine susceptibilities of primary human immunodeficiency
virus type 1 isolates with non-B subtypes or nucleoside resistance. AIDS Res Hum
Retroviruses 2001;17 (12):1167-73.
5125
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al.
Changing patterns of mortality across Europe in patients infected with HIV-1.
Lancet 1998;352 (9142):1725-30.
CONFIDENTIAL
Page 173
18AUG2010
Final
5482
Wolf K, Walter H, Beerenwinkel N, Keulen W, Kaiser R, Hoffmann D, et al.
Tenofovir resistance and resensitization. Antimicrob Agents Chemother 2003;47
(11):3478-84.
6043
Taburet AM, Piketty C, Gerard L, Vincent I, Chazallon C, Clavel F, et al.
Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in
HIV infected patients with multiple treatment failures: a sub-study of Puzzle2ANRS 107 Trial [poster]. 10th Conference on Retroviruses and Opportunistic
Infections; 2003 February 10-14; Boston, Mass, USA. Poster 537.
6054
Ray A, Olson L, Fridland A. Role of purine nucleoside phosphorylase in drug
interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir or tenofovir.
6074
Domingo P, Labarga P, Llibre JM, Guerrero MF, Terron JA, Elias MJP, et al.
Dyslipidaemia improvement in patients switching from D4T to tenofovir. (Recover
Study) [abstract]. 9th Conference of the European AIDS Clinical Society; 2003
October 24-28; Warsaw, Poland.
6133
Glesby MJ. Bone disorders in human immunodeficiency virus infection. Clin
Infect Dis 2003;37 (Suppl 2):S91-S5.
6134
DeJesus E, Grinsztejn B, Rodriguez C, Nieto L, Coco J, Lazzarin A, et al. Efficacy
and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) vs
lopinavir/ritonavir (LPV/RTV) in patients who have experienced virologic failure
on multiple HAART regimens: 48-week results from BMS AI424-045 [abstract].
11th Conference on Retroviruses and Opportunistic Infections; 2004 February 811; San Francisco, Calif, USA.
6137
Cheng AK, Chen SS, Wulfsohn M, Toole JJ. 2 year long term safety profile of
tenofovir DF (TDF) in treatment-experienced patients from randomized, doubleblind, placebo-controlled clinical trials [poster]. 9th European AIDS Conference
(EACS); 2003 October 25-29; Warsaw, Poland. Poster Number 7.3/7.
6180
Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, et al. Increasing
mortality due to end-stage liver disease in patients with human immunodeficiency
virus infection. Clin Infect Dis 2001;32 (3):492-7.
6181
Dore GJ, Cooper DA. The impact of HIV therapy on co-infection with hepatitis B
and hepatitis C viruses. Curr Opin Infect Dis 2001;14 (6):749-55.
6266
Videx EC (SmPC). Bristol-Myers Squibb Pharmaceuticals. Hounslow. 06
January 2003.
6379
Benhamou Y, Piketty C, Katlama C, Rozembaum W, Neau D, Lafeuillade C, et al.
Anti-hepatitis B virus (HBV) activity of tenofovir disoproxil fumarate (TDF) in
CONFIDENTIAL
Page 174
18AUG2010
Final
human immunodeficiency virus (HIV) co-infected patients [poster]. 54th Annual
Meeting of the AASLD; 2003 October 24-28; Boston, Mass, USA. Poster 1155.
6389
Lok ASF, McMahon BJ. Chronic hepatitis B: update of recommendations.
Hepatology 2004;39 (3):857-61.
6586
Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy
of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced
patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004;189
(7):1185-92.
6772
Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal
dysfunction with tenofovir DF containing HAART regimens is not observed more
frequently: a cohort and case control study [poster]. 10th Anniversary Conference
of the British HIV Association (BHIVA); 2004 April 15-17; Cardiff, United
Kingdom.
6837
Stephan C, Berger A, Lutz T, Stuermer M, Nisius G, Carlebach A, et al. Impact of
tenofovir on chronic hepatitis B in HIV co-infected individuals: The Frankfurt
Cohort Study Experience [poster]. 43rd Interscience Conference on Antimicrobial
Agents and Chemotherapy; 2003 September 14-17; Chicago, Ill, USA. Poster V784.
6849
Park J, Braun J, Kreiswirth S, Goldman D, Mullen M, Dieterich D. Co-infection
with HIV and HBV: The Effect of Tenofovir Disoproxil Fumarate in Lamivudine
and Famciclovir Experienced Patients [AASLD Abstract No. 1911]. Hepatology
2002;36 (4, Pt. 2):641A.
6923
Podzamczer D, Ferrer E, Gatell JM, Niubo J, Dalmau D, Leon A, et al. Early
virologic failure with a combination of tenofovir, didanosine and efavirenz
[Poster]. International Resistance Workshop; 2004 June; Tenerife, Spain.
7013
Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JMAH, Miller MD, et
al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in
antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292 (2):191201.
7034
Maggiolo F, Migliorino M, Maserati R, Rizzi L, Pan A, Rizzi A, et al. Once-a-day
treatment for HIV infection: Final 48-week results. 8th Conference on Retroviruses
and Opportunistic Infections; 2001 February 4-8; Chicago, IL. Abstract 320.
7035
Felizarta F, Becker S, Bellos N, Jayaweera D, Sands M, Slater L, et al. Adherence
and efficacy with a once-daily efavirenz-based regimen: 48-week results from the
Daily Antiretroviral Therapy II (DART II) Study [poster 5842]. XV International
AIDS Conference; 2004 July 11-16; Bangkok, Thailand.
CONFIDENTIAL
Page 175
18AUG2010
Final
7036
Arribas JR, Iribarren JA, Knobel H, Ribera E, Rubio R, Viciana P, et al.
Adherence, treatment satisfaction and effectiveness of once-daily (QD) vs twicedaily (BID) antiretroviral therapy (AT), in a large prospective observational cohort
(CUVA Study) [poster WePeB5780]. XV International AIDS Conference; 2004
July 11-16; Bangkok, Thailand.
7299
Cihlar T, Bleasby K, Roy A, Pritchard J. Antiviral acyclic nucleotide analogs
tenofovir and adefovir are substrates for human kidney organic anion, but not
cation transporters: implications for potential renal drug interactions [poster A443]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy;
2004 October 30-November 2; Washington, DC, USA.
7325
Moyle G, Maitland D, Hand J, Mandalia S, Nelson M, Gazzard B. Early
virological failure in persons with viral loads >100000 copies/ml and CD4 counts
<200/mm3 receiving didanosine/tenofovir/efavirenz as initial therapy: 12 week
results from a randomized comparative trial [poster H-566]. 44th Interscience
Conference on Antimicrobial Agents and Chemotherapy; 2004 October 30November 2; Washington, DC, USA.
7358
Johnson M, DeJesus E, Grinsztejn B, Rodriguez C, Nieto-Cisneros, Coco J, et al.
Long-term efficacy and durability of atazanavir (ATV) with ritonavir (RTV) or
saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in HIV-infected patients
with multiple virologic failures: 96-week results from a randomized, open-label
trial, BMS A1424045 [poster #PL14.4]. Seventh International Congress on Drug
Therapy in HIV Infection; 2004 November 14-18; Glasgow, UK.
7374
Johnson M, De Jesus E, Grinsztein B. Comparison of Atazanavir (ATV) with
Ritonavir or Saquinavir vs Lopinavir/ritonavir in Patients with Multiple Virologic
Failures: BMS AI424-045 96 Week Results. Long-term Efficacy and Durability of
Atazanavir With Ritonavir or Saquinavir vs Lopinavir/Ritonavir in HIV-Infected
Patients With Multiple Virologic Failures (Oral presentation PL14.4). 7th
International Congress on Drug Therapy in HIV Infection; 2004 November 14-18;
Glasgow, UK.
7399
Hodder SL. Bristol-Myers Squibb Company letter to physicians about clinical
data: Potential Early Virologic Failure Associated with the Combination
Antiretroviral Regimen of Tenofovir Disoproxil Fumarate, Didanosine, and Either
Efavirenz or Nevirapine in HIV Treatment-Naive Patients with High Baseline
Viral Loads. November 2004.
7469
Peters M, Andersen J, Lynch P, Jacobson JM, Sherman K, Alston-Smith B, et al.
Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment
of Hepatitis B virus in subjects who are co-infected with HIV: Results of ACTG
A5127 [oral abstract 124]. 12th Conference on Retroviruses and Opportunistic
Infections (CROI); 2005 February 22-25; Boston, MA.
CONFIDENTIAL
Page 176
18AUG2010
Final
7625
Becker SL, Balu RB, Fusco JS, Fusco GP. Beyond serum creatinine: Identification
of renal insufficiency using GFR: Implications for clinical research and care
[poster 819]. 12th Conference on Retroviruses and Opportunistic Infections; 2005
February 22-25; Boston, Mass, USA.
7672
Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function
associated with tenofovir disoproxil fumarate treatment, compared with nucleoside
reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40 (8):1194-8.
7725
Harris M, Zalunardo N, Yip B, Werb R, Valyi M, Hogg R, et al. Nephrotoxicity of
tenofovir DF in an expanded access program [oral presentation]. Presented at the
12th Annual Canadian Conference on HIV/AIDS Research; 2003 April 10-13;
Nova Scotia, Canada.
7760
Llibre JM, Domingo P, Perez MJ, Labarga P, Palacios R, Ruiz MI, et al.
Continuous improvement of dyslipidemia in patients with baseline hyperlipidemia
switching from D4T to tenofovir: 24 week data (Recover Study) [poster abstract
268]. 7th International Congress on Drug Therapy in HIV Infection; 2004
November 14-18; Glasgow, UK.
7932
Palacios R, Santos J, Domingo P, Elizas MJP, Arazo P, Miralles C, et al. Impact of
switching from stavudine (d4T) to tenofovir DF (TDF) on cardiovascular (CV) risk
factors in patients with lipoatrophy (LIPO-REC study) [poster TuPe2.3C15]. 3rd
International AIDS Society Conference on HIV Pathogenesis and Treatment; 2005
July 24-27; Rio de Janeiro, Brazil.
7974
Molina JM, Wilkin A, Domingo P, Myers R, Hairrell J, Naylor C, et al. Once-daily
vs. twice-daily lopinavir/ritonavir in antiretroviral-naïve patients: 96-week results
[poster WePe12.3C12]. 3rd International AIDS Society Conference on HIV
Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro, Brazil.
7987
Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function in
patients treated with Tenofovir DF (TDF) compared to nucleoside reverse
transcriptase inhibitors (NRTIs) [abstract]. 3rd International AIDS Society
Conference on HIV Pathogenesis and Treatment; 2005 July 24-27; Rio de Janeiro,
Brazil.
8056
Jones R, Stebbing J, Nelson M, Moyle G, Bower M, Mandalia S, et al. Renal
dysfunction with tenofovir disoproxil fumarate-containing highly active
antiretroviral therapy regimens is not observed more frequently: a cohort and casecontrol study. J Acquir Immune Defic Syndr Hum Retrovirol 2004;37 (4):1489-95.
8115
Powderly W, Cohen C, Gallant J, Lu B, Enejosa J, Cheng AK, et al. Similar
incidence of osteopenia and osteoporosis in antiretroviral-naïve patients treated
with tenofovir DF or stavudine in combination with lamivudine and efavirenz over
144 weeks [poster number 823]. 12th Conference on Reteroviruses and
Opportunistic Infections; 2005 February 22-25; Boston, Mass, USA.
CONFIDENTIAL
Page 177
18AUG2010
Final
8284
Sterne JAC, Hernán MA, Ledergerber B, Tilling K, Weber R, Sendi P, et al. Longterm effectiveness of potent antiretroviral therapy in preventing AIDS and death: a
prospective cohort study. Lancet 2005;366 (9483):378-84.
8344
Zerai T, El-Sahly H, Andrade R, Munoz C, Nnabuife C, Hunter R. Effects of
tenofovir DF on the kidney [poster 093]. 43rd Annual Meeting of the Infectious
Diseases Society of America (IDSA); 2005 October 6-9; San Francisco, Calif,
USA.
8414
Staszewski S, Pozniak AL, Lu B, Cotton G, Enejosa J, Cheng AK. Similar Renal
Safety Profile Between Tenofovir DF (TDF) and Stavudine (d4T) Using
Modification of Diet in Renal Disease (MDRD) and Cockroft-Gault (CG)
Estimation of Glomerular Filtration Rate (GFR) in Antiretroviral-Naïve Patients
Through 144 Weeks [poster]. 7th International Workshop on Adverse Drug
Reactions and Lipodystrophy in HIV; 2005 November 13-16; Dublin, Ireland.
Poster Number 93.
8418
Ray AS, Vela JE, Robinson KL, Cihlar T, Rhodes GR. Efflux of Tenofovir by the
Multidrug Resistance-Associated Protein 4 (MRP4) is not Affected by HIV
Protease Inhibitors [poster]. 7th International Workshop on Adverse Drug
Reactions and Lipodystrophy in HIV; 2005 November 13-16; Dublin, Ireland.
Poster Number 91.
8646
Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P.
Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination
but not the intestinal disposition of tenofovir disoproxil fumarate and its
metabolites. Xenobiotica 2005;35 (10-11):1055-66.
8715
Heffelfinger JD, Hanson DL, Voetsch AC, McNaghten AD, Sullivan PS. Renal
impairment associated with the use of tenofovir [poster 779]. 13th Conference on
Retroviruses and Opportunistic Infections; 2006 February 5-9; Denver, Colo,
USA.
8904
Ray AS, Tong L, Robinson KL, Kearney BP, Rhodes GR. Role of intestinal
absorption in increased tenofovir exposure when tenofovir disoproxil fumarate is
co-administered with atazanavir or lopinavir/ritonavir [poster number 49]. 7th
International Workshop on Clinical Pharmacology of HIV Therapy; 2006 April
20-22; Lisbon, Portugal.
8920
Walker UA, McComsey GA. Mitochondrial Toxicity of Nucleoside Analogs. In:
Hoffmann C, Rockstroh JK, Kamps BS, eds. HIV Medicine 2005. Paris, France:
Flying Publisher; 2005: 299-309.
9005
Cote HC, Magil AB, Harris M, Scarth BJ, Gadawski I, Wang N, et al. Exploring
mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction
among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther
2006;11 (1):79-86.
CONFIDENTIAL
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18AUG2010
Final
9023
Winston A, Amin J, Mallon P, Marriott D, Carr A, Cooper DA, et al. Minor
changes in calculated creatinine clearance and anion-gap are associated with
tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV
Med 2006;7 (2):105-11.
9115
O'Flaherty EJ. Modeling normal aging bone loss, with consideration of bone loss
in osteoporosis. Toxicol Sci 2000;55 (1):171-88.
9116
Powderly WG. Bone disorders in HIV-infected patients. Medscape General
Medicine 2001; 3(1). Available at:.
http://www.medscape.com/viewarticle/403863_print. Accessed June 16, 2006.
9161
Moreno S, Domingo P, Palacios R, Santos J, Falco V, Murillas J, et al. Renal
Safety of Tenofovir Disoproxil Fumarate in HIV-1 Treatment-experienced Patients
with Adverse Events Related to Prior NRTI Use: Data from a Prospective,
Observational, Multicenter Study. J Acquir Immune Defic Syndr Hum Retrovirol
2006;42 (3):385-7.
9266
Delaney WE, IV, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular
metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob
Agents Chemother 2006;50 (7):2471-7.
9318
Ray AS, Cihlar T, Robinson KL, Tong L, Vela JE, Fuller MD, et al. Mechanism of
active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 2006;50
(10):3297-304.
9334
Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al.
Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed
and TDF-unexposed HIV-infected out-patients receiving highly active
antiretroviral therapy. HIV Med 2006;7 (7):451-6.
9863
Cihlar T, Ray A, Laflamme G, Vella J, Tong L, Fuller M, et al. Molecular
assessment of the potential for renal drug interactions between tenofovir and HIV
protease inhibitors. Antivir Ther 2007;12 (2):267-72.
9864
Vidal F, Domingo JC, Guallar J, Saumoy M, Cordobilla B, Sanchez de la Rosa R,
et al. In vitro cytotoxicity and mitochondrial toxicity of tenofovir alone and in
combination with other antiretrovirals in human renal proximal tubule cells.
10259
Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, et al.
Association between ABCC2 Gene Haplotypes and Tenofovir-Induced Proximal
Tubulopathy. J Infect Dis 2006;194 (11):1481-91.
CONFIDENTIAL
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10260
Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y.
Functional involvement of multidrug resistance associated protein 4
(MRP4/ABCC4) in the renal elimination of the anti-viral drugs, adefovir and
tenofovir. Mol Pharmacol 2007;71 (2):619-27.
10394
Buchacz K, Young B, Baker RK, Moorman A, Chmiel JS, Wood KC, et al. Renal
Function in Patients Receiving Tenofovir With Ritonavir/Lopinavir or
Ritonavir/Atazanavir in the HIV Outpatient Study (HOPS) Cohort. J Acquir
Immune Defic Syndr 2006;43 (5):626-8.
10610
Tong L, Phan TK, Robinson KL, Rhodes GR, Ray AS. Role of intestinal
absorption in changes in tenofovir exposure when tenofovir disoproxil fumarate is
co-administered with certain HIV protease inhibitors [abstract]. AAPS Workshop
on Drug Transporters in ADME: From the Bench to the Bedside; 2007 March 5-7;
North Bethesda, Md, USA.
10611
Tong L, Phan TK, Robinson KL, Rhodes GR, Ray AS. Role of intestinal
absorption in changes in tenofovir exposure when tenofovir disoproxil fumarate is
co-administered with certain HIV protease inhibitors [poster number 59]. AAPS
Workshop on Drug Transporters in ADME: From the Bench to the Bedside; 2007
March 5-7; North Bethesda, Md, USA.
10921
Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The
safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults:
the first 4 years. AIDS 2007;21 (10):1273-81.
10960
de la Prada FJ, Prados AM, Tugores A, Uriol M, Saus C, Morey A. Insuficiencia
renal aguda y disfuncíon tubular proximal en paciente diagnosticado de infeccíon
VIH tratado con tenofovir [Spanish]. Nefrologia 2006;26 (5):626-30.
11255
Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, et al. Effects
of human immunodeficiency virus protease inhibitors on the intestinal absorption
of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother 2007;51
(10):3498-504.
11576
Andreev E, Koopman M, Arisz L. A rise in plasma creatinine that is not a sign of
renal failure: which drugs can be responsible? J Intern Med 1999;246 (3):247-52.
12007
Hynes P, Urbina A, McMeeking A, Barisoni L, Rabenou R. Acute renal failure
after initiation of tenofovir disoproxil fumarate. Renal failure 2007;29 (8):1063-6.
12230
Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, Fletcher CV. Clinical
and genetic determinants of intracellular tenofovir diphosphate concentrations in
HIV-infected patients. J Acquir Immune Defic Syndr 2008;47 (3):298-303.
CONFIDENTIAL
Page 180
18AUG2010
Final
12344
Kiser JJ, Carten ML, Aquilante CL, Anderson PL, Wolfe P, King TM, et al. The
effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected
patients. Clin Pharmacol Ther 2008;83 (2):265-72.
12554
Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J,
et al. Efficacy and safety of once-daily darunavir/ritonavir versus
lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS
2008;22 (12):1389-97.
12654
ZIAGEN (abacavir sulfate) Tablets. ZIAGEN (abacavir sulfate) Oral Solution.
US Prescribing Information. GlaxoSmithKline. Research Triangle Park, NC. July
2008
12702
Gallant JE, Pozniak AL, DeJesus E, Chen SS, Cheng AK, Enejosa J. Renal safety
profile of tenofovir DF (TDF)-containing vs. thymidine analog-containing
regimens through 144 weeks in antiretroviral-naive patients [poster number
THPE0186]. XVII International AIDS Conference; 2008 August 3-8; Mexico City,
Mexico.
12716
Hammer SM, Eron JJ, Jr., Reiss P, Schooley RT, Thompson MA, Walmsley S, et
al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the
International AIDS Society-USA panel. JAMA 2008;300 (5):555-70.
12896
UNAIDS. Report on the global AIDS epidemic: Executive summary. July, 2008.
13428
Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, et
al. Update of the Drug Resistance Mutations in HIV-1:December 2008. Top HIV
Med 2008;16 (5):138-45.
13786
Lebrecht D, Venhoff AC, Kirschner J, Wiech T, Venhoff N, Walker UA.
Mitochondrial Tubulopathy in Tenofovir Disoproxil Fumarate-Treated Rats. J
Acquir Immune Defic Syndr 2009;00 (0).
14064
Levin J. The effect of different types of food on the bioavailability of TMC278, an
investigational NNRTI. 9th International Workshop on Clinical Pharmacology of
HIV Therapy; 2008 April 7-9; New Orleans, Louisiana, USA.
14065
Gazzard BG. British HIV Association Guidelines for the treatment of HIV-1infected adults with antiretroviral therapy 2008. HIV Med 2008;9 (8):563-608.
14196
Woodward CL, Hall AM, Williams IG, Madge S, Copas A, Nair D, et al.
Tenofovir-associated renal and bone toxicity. HIV Med 2009;10 (8):482-7.
14246
Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al.
Safety and efficacy of raltegravir-based versus efavirenz-based combination
therapy in treatment-naive patients with HIV-1 infection: a multicentre, doubleblind randomised controlled trial. Lancet 2009;374 (9692):796-806.
CONFIDENTIAL
Page 181
18AUG2010
Final
14978
Rodriguez-Novoa S, Labarga P, Soriano V, Egan D, Albalater M, Morello J, et al.
Predictors of kidney tubular dysfunction in HIV-infected patients treated with
tenofovir: a pharmacogenetic study. Clin Infect Dis 2009;48 (11):e108-16.
15040
ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate) tablets. US
Prescribing Information. Gilead Sciences and Bristol-Myers Squibb, LLC. Foster
City, CA. January 2010.
15207
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the
use of antiretroviral agents in HIV-1-infected adults and adolescents. Department
of Health and Human Services. December 1, 2009; 1-161. Available at
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
15280
Kirk O, Mocroft A, Reiss P, De Wit S, Sedlacek D, Beniowski M, et al. Chronic
Kidney Disease and Exposure to ART in a Large Cohort with Long-term Followup: The EuroSIDA Study [Abstract 107LB]. 17th Conference on Retroviruses and
Opportunistic Infections (CROI); 2010 February 16-19; San Francisco, CA.
15430
Pushpakom S, Liptrott N, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M,
et al. Genetic Variants of ABCC10 Are Associated with Kidney Tubular
Dysfunction in Patients Treated with Tenofovir-containing Regimens [Poster 742].
17th Conference on Retroviruses and Opportunistic Infections (CROI); 2010
February 16-19; San Francisco, CA.
15541
Azijn H, Tirry I, Vingerhoets J, de Béthune M, Kraus G, Boven K, et al. TMC278,
a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI),
Active against Wild-Type and NNRTI-Resistant HIV-1. Antimicrob Agents
Chemother 2010;54 (2):718-27.
15807
SUSTIVA (efavirenz) capsules and tablets. US Prescribing Information. BristolMyers Squibb Company. Princeton, NJ. March 2010.
15851
Dharnidharka VR, Kwon C, Stevens G. Serum cystatin C is superior to serum
creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis
2002;40 (2):221-6.
15864
Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al.
Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled
48 week analysis of two randomized, controlled trials. AIDS 2009;23 (17):2289300.
15869
Lima VD, Gill VS, Yip B, Hogg RS, Montaner JS, Harrigan PR. Increased
resilience to the development of drug resistance with modern boosted protease
inhibitor-based highly active antiretroviral therapy. J Infect Dis 2008;198 (1):51-8.
CONFIDENTIAL
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15873
Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David
N, et al. Once-daily atazanavir/ritonavir compared with twice-daily
lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for
management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and
safety results of the CASTLE study. J Acquir Immune Defic Syndr 2010;53
(3):323-32.
15884
Swan SK. The search continues--an ideal marker of GFR. Clin Chem 1997;43 (6
Pt 1):913-4.
15965
European AIDS Clinical Society (EACS) Guidelines for the Clinical Management
and Treatment of HIV Infected Adults in Europe. Version 5.2. 1-25.
15966
ISENTRESS (raltegravir) Tablets. US Prescribing Information. Merck & Co., Inc.
Whitehouse Station, NJ. Revised December 2009.
15967
RESCRIPTOR (brand of delavirdine mesylate tablets), US Prescribing
Information. Agouron Pharmaceuticals Inc. LaJolla, CA, Revised May 2001.
15968
SELZENTRY (maraviroc) tablets. US Prescribing Information. Pfizer Labs,
New York, NY. November 2009.
15969
Viramune (nevirapine) tablets, 200 mg. US Prescribing Information. Boehringer
Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. Revised January 2010.
CONFIDENTIAL
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2.5.8.
Final
List of Gilead Nonclinical and Clinical Reports
Table 31 provides a list of all Gilead nonclinical studies for FTC, TDF, FTC/TDF, and
EFV/FTC/TDF. All nonclinical studies considered pivotal to support this MAA are provided
within Module 4 as outlined within the table. Table 32 provides a list of all clinical studies
conducted for FTC, TDF, FTC/TDF, and EFV/FTC/TDF. All clinical studies considered
pivotal to support this MAA are provided within Module 5 as outlined within the table.
Reports for studies that are not provided in this submission are available on request within
48 hours (as they are not considered pivotal to the FTC/RPV/TDF FDC and have previously
been submitted and reviewed within the context of the MAAs for Emtriva [EMEA/H/C/533],
Viread [EMEA/H/C/419], Truvada [EMEA/H/C/594] and Atripla [EMEA/H/C/797]).
Reports for studies relating to RPV and the FTC/RPV/TDF FDC (all considered pivotal to
this submission) are located in Modules 4 (nonclinical) and 5 (clinical) are not included
within these tables.
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Table 31.
Final
Gilead Nonclinical Reports
Cross-Reference to Study Report
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TESF/91/0014
Phosphorylation of 523W91 and
524W91 by calf thymus
deoxycytidine kinase
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TESF/92/0002
Kinetic constants for 523W91 and
524W91 with calf thymus
deoxycytidine kinase
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TEIT/92/0005
Phosphates of 523W91 and 524W91:
results with dCPMP kinase
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TGZZ/93/0025
Phosphorylation of the 5’
monophosphate of 524W91 to the
5’-Di-and 5’triphosphates by cellular
enzymes
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TPI 15883
Activity of emtricitabine on the HIV1 reverse transcriptase mutant K65R;
biochemical and phenotypic analysis
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
TEZA/92/0062
Anabolism of (-) 3’Thia-2’,3’dideoxy-5-[6-3H]fluorocytidine
(524W91,(-) FTC) and (+)3’-Thia2’,3’-dideoxy-5-[6-3H]fluorocytidine
(524W91, (+)FTC) in Hep G2 2.2.15
(P5A) Cells
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
CONFIDENTIAL
Page 185
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TEZA/92/0103
Anabolism of (-) 3’-Thia-2’,3’dideoxy-5-[6-3H]fluorocytidine
(524W91, (-) FTC) in CEM Tlymphoblast cells
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TEZA/92/0111
Anabolism of (-) 3’-Thia-2’,3’dideoxy-5-[6-3H]fluorocytidine
(524W91, (-) FTC) in Hep G2
(human hepatocellular carcinoma)
cells
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TEZZ/93/0007
Inhibition of HeLa DNA
polymerases Į, ȕ, Ȗ and İ and HIV-1
reverse transcriptase by the
triphosphates of ddC (16Y82), (+)
FTC (523W91), (-) FTC (524W91),
(+) 3TC (1960U90) and (-)3TC
(1961U90)
Emtriva
Avaliable
upon request
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 21
TPI 11985
Effect of orally administered
emtricitabine [(-)-FTC] and
lamivudine [3TC] in the HuPBMCSCID mouse model of HIV-1
infection
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TPI 462 v2
Antiviral activity of FTC, (2R-cis)-4amino-5-fluoro-1-[2(hydroxymethyl)-1,3-oxathiolan-5yl]-2(1H)-pyrimidinone against
HIV-1
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
CONFIDENTIAL
Page 186
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
TPI 10498 v2
Evaluation of the antiviral activity of
emtricitabine against HIV-1 (Group
M and Subtype O) and HIV-2
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
10518-v2
MAGI-LU assay validation 1:
Inhibitory effect of FTC on HIV-1
xxLAI viral infection is independent
of multiplicity of infection (MOI) of
the infecting virus
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
11773
Effect of multiplicity of infection on
inhibition of HIV-1 replication by
FTC
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
10247
DXG, FTC, and AZT: time of
addition
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
463
Effect of human serum on the antiHIV-1 activity of FTC, (2R-cis)-4amino-5-fluoro-1-[2(hydroxymethyl)-1,3-oxathiolan-5yl]-2(1H)-pyrimidinone
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
TPI 11419 v2
Evaluation of the antiviral activity of
emtricitabine against HIV-1 (group
M and subtype O) and HIV-2 using
the MAGI-LU assay in cMAGI cells
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
TPI 11148
Phenotypic evaluation of FTC, DXG
and MKC442 on recombinant
clinical isolates of HIV-1
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 2
CONFIDENTIAL
Page 187
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TPI 9501
Inhibition of human mitochondrial
DNA polymerase by (+) FTC, (-)
FTC, and DXG triphosphates
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
P4331-00035
In vitro drug sensitivity of
nucleoside and non-nucleoside
reverse transcriptase inhibitor
resistant clinical HIV-1 isolates to
tenofovir
Viread
Module
4.2.1.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 24
PC-104-2003
In vitro activity of tenofovir against
HIV-2
Truvada
Module
4.2.1.1
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
PC-104-2004
Effects of the K65R mutation on
HIV-1 replication capacity
Truvada
Module
4.2.1.1
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 1
PC-104-2008
In vitro phosphorylation of tenofovir
and abacavir
Viread
Available
upon request
Provided in 3rd
Annual Risk
Benefit
(EMEA/H/C/419/S/
48)
February 2005
3rd Annual
Risk Benefit
Volume 5
PC-104-2013
Antiviral activity vs. HIV-1 & HIV2
Viread
Module
4.2.1.1
Previously not
submitted.
PC-104-2017
Susceptibility to tenofovir and
tenofovir disoproxil fumarate
(tenofovir DF) of virologic failure
isolates from study GS-01-934
Viread
Module
4.2.1.1
Previously not
submitted.
CONFIDENTIAL
Page 188
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
PC-164-2007
Week 144 virology report of study
GS-01-934
Truvada
Available
upon request
Provided in Type II
variation
(EMEA/H/C/594
II/036)
October 2007
Module 5
Volume 1
P0393-00025
Tenofovir, adefovir and zidovudine
susceptibilities of human
immunodeficiency virus type I
isolates with non-B subtypes or
nucleoside resistance
Viread
Available
upon request
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 23
PC-164-2001
In vitro phosphorylation of tenofovir
and emtricitabine
Truvada
Module
4.2.1.1
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 2
PC-164-2005
In vitro resistance selection with
tenofovir and emtricitabine
Truvada
Available
upon request
Submitted in PSUR
(03 February 2005
to 12 August 2005)
September
2005
PSUR
Volume 2
233
Data from clonogenic assays CFUGM and BFU-E and mitochondrial
assays for TP0001 and TP0004 as
compared to AZT
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 4
TPI 11963
An in vitro evaluation of the effects
on cell growth and mitochondrial
functions in the MT2 cell line after
long term exposure to antiviral
xenobiotics
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 4
CONFIDENTIAL
Page 189
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TGZZ/93/0016
Effect of antiviral nucleoside
analogues on mitochondrial DNA
synthesis in Molt-4 cells
Truvada
Module
4.2.2.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
TGZZ/93/0023
Effect of 524W91 on mitochondrial
DNA synthesis on Molt-4 cells
Truvada
Module
4.2.3.1
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
P4331-00038
Activity of tenofovir and tenofovir
disoproxil fumarate against hepatitis
B virus in cell culture
Viread
Module
4.2.1.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 24
PC-104-2012
Antiviral activity against hepatitis B
virus with the rtA194T mutation
Viread
Module
4.2.1.2
Provided in Type II
variation
(EMEA/H/C/419
/II/75)
October 2007
Module 5
Volume 1
PC-174-2003
In vitro susceptibility of HBV
rtA194T mutants to tenofovir
Viread
Module
4.2.1.2
Provided in Type II
variation
(EMEA/H/C/419
/II/75)
October 2007
Module 5
Volume 1
C4331-00013
(P4331-00037)
In vitro cytotoxicity of tenofovir in
various human cell types comparison with other NRTIs
Viread
Available
upon request
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 24
P1278-00042
In vitro assessment of tenofovir
mitochondrial toxicity – comparison
with approved NRTIs
Truvada
Module
4.2.1.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 4
CONFIDENTIAL
Page 190
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TX-104-2001
Mitochondrial toxicity of
combinations of nucleoside and
nucleotide analogue reversetranscriptase inhibitors in HepG2
cells
Viread
Module
4.2.1.2
Provided in
response to CHMP
request
EMEA/CPMP
/5836/03
July 2005
Response
document
Volume 1
PC-174-2004
A 48-week oral dosing study of
adefovir dipivoxil (ADV), tenofovir
disoproxil fumarate (TDF),
emtricitabine (FTC), and lamivudine
93TC) alone and in combination
using the woodchuck model of
hepatitis B virus infection
Viread
Module
4.2.1.2
Provided in Type II
variation
(EMEA/H/C/419/
II/75)
February 2007
Type II
variation
Volume 1
PC-164-2004
In vitro combination testing of
tenofovir and emtricitabine against
hepatitis B virus
Viread
Available
upon request
Provided in Type II
variation
(EMEA/H/C/419/
II/75)
October 2007
Module 5
Volume 1
TPZZ/93/0002
In vitro receptor binding potencies of
524W91
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/92/0055
In vitro autonomic pharmacology of
524W91 and its effects on peripheral
autonomic receptors
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/92/0056
Effects of 524W91 on isolated
cardiac muscle of rat, guinea-pig and
cat
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
CONFIDENTIAL
Page 191
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
477
General high dose testing results for
FTC
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/93/0001
General pharmacology of 524W91
over an extended dose range in mice
and rats
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/93/0119
Effects of 524W91 on conditioned
avoidance responce in rats
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/92/0057
Effects of 524W91 on systolic blood
pressure and heart rate of conscious
normotensive rats
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
TPZZ/92/0076
Effects of intravenous injection of
524W91 on cardiovascular,
respiratory and autonomic function
in anaesthetized dogs
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
V2000020
Spectrum screen of GS-4331-05 and
GS-1278
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
V2000009
Guinea pig ileum contractile
response
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
R990152
A pharmacological safety assessment
of the effect of tenofovir DF (GS4331-05) on the central nervous
system of the rat
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 5
CONFIDENTIAL
Page 192
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
R990153
A pharmacological assessment of the
effect of tenofovir DF (GS-4331-05)
on gastrointestinal motility in the rat
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
R990154
A pharmacological assessment of the
effect of tenofovir DF (GS-4331-05)
on the renal system of the rat
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
D990155
Cardiovascular profile study
following a single oral
administration of tenofovir DF in the
unrestrained conscious beagle dog
Truvada
Module
4.2.1.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
470
In vitro synergy studies of FTC in
combination with MKC 442, AZT,
nelfinavir (NELF) and nevirapine
(NEV) against HIV
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/ 594)
March 2004
Module 4
Volume 2
10804
In vitro synergy studies with FTC
and other anti-HIV compounds
Emtriva
Module
4.2.1.4
Included in
response to CPMP
Day 120 List of
Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume 3
12207
Synergy of emtricitabine (FTC) and
lamivudine (3TC) in combination
with stavudine (d4T) and nevirapine
(NVP) against HIV
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
C1278-00005
In vitro synergy of tenofovir
combinations against HIV-1
Viread
Module
4.2.1.4
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 23
CONFIDENTIAL
Page 193
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
PC-104-2005
Tenofovir, abacavir and lamivudine;
evaluation of the in vitro anti-HIV
activity of the combination in PBMC
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 2
PC-104-2006
Tenofovir, didanosine and
lamivudine; evaluation of the in vitro
anti-HIV activity of the combination
in PBMC
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 2
PC-104-2007
In vitro combination studies of
tenofovir and other nucleoside
analogs with ribavirin against HIV-1
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 6
PC-183-2004
Antiviral activity in combination
with other antiretroviral drugs
Viread
Module
4.2.1.4
Previously not
submitted
14379
In vitro synergy studies with
emtricitabine and tenofovir
Emtriva
Module
4.2.1.4
Included in
Response to CPMP
Day 120 List of
Questions
(EMEA/H/C/533)
May 2003
Follow-up
Measure
Volume 3
PC-164-2002
In vitro anti-HIV synergy studies of
tenofovir and emtricitabine
Truvada
Module
4.2.1.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 2
1010
Determination of TP-0006/96 in
human, mouse and monkey plasma
and human urine by HPLC-MS
(SIM)
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
CONFIDENTIAL
Page 194
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
6159v1
Determination of emtricitabine in
mouse, monkey and rabbit plasma by
LC/MS/MS
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
7582v1
human or monkey urine by
LC/MS/MS
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
6447v5
human and rat plasma using
LC/MS/MS
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
P4331-00009
Validation of a high performance
liquid chromatographic method for
the determination of GS-4331-05 in
dose formulations
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 7
P4331-00008:
97-TOX-4331008
Cross-validation of an HPLC method
for the quantitation of GS-1278
(PMPA) in mouse plasma and
determination of PMPA in mouse
plasma samples
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 7
P1278-00001
(OLI-VRA144.1)
Validation of an HPLC assay for the
quantitation of GS-1278 (PMPA) in
rat plasma and cross-validation in
cynomolgus monkey plasma
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 7
CONFIDENTIAL
Page 195
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
P1278-00028
(001097/NDK)
liquid chromatographic mass
spectrometric method for the
determination of GS-1278 (RPMPA) in rat plasma (sodium
citrate) - cross validation of GS-1278
(R-PMPA) in rat plasma (heparin) cross validation of GS-1278
(R-PMPA) in mouse plasma (sodium
heparin)
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
P1278-00034:
Project No.
003105OU1
determination of GS-1278 in rat milk
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
P4331-035-3
(Oread No:
OLI-RE7489901-DNS-1)
Cross validation of an HPLC method
(PMPA) in rabbit plasma and
determination of PMPA in rabbit
samples (from study 98-TOX-4331005)
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
P1278-00017
Cross-validation of an HPLC assay
(PMPA) in dog plasma
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
CONFIDENTIAL
Page 196
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
P4331-0037
(MDS Project
No.
003296OTN)
Mini-validation of a high
performance liquid chromatographic
mass spectrometric method for the
determination of GS-1278 (RPMPA) in dog plasma (EDTA)
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
P1278-00029
(MDSPS
Project No:
002092OFH)
determination of GS-1278 (RPMPA) in monkey plasma (EDTA)
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 8
TEIN/93/0003
Pharmacokinetics of 524W91 in
male CD-1 mice following oral and
intravenous administration
Emtriva
Module
4.2.2.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 22
TEIN/93/0004
Pharmacokinetics of 100 mg/kg oral
and intravenous 524W91 in male
CD-1 mice
Emtriva
Module
4.2.2.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 22
IUW00101
Pharmacokinetic study in male mice
following single oral and intravenous
administration of L-(-)-2’3’-dideoxy5-fluoro-3’-thiacytidine
Truvada
Module
4.2.2.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 10
TEZZ/93/0019
A pharmacokinetic study of 524W91
in cynomolgus monkeys following
oral and intravenous administration
Emtriva
Module
4.2.2.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 22
CONFIDENTIAL
Page 197
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
IUW00301
Pharmacokinetic study in
cynomolgus monkeys following
single oral and intravenous
administration of L-(-)-2’,3’dideoxy-5-fluoro-3’thiacytidine
Emtriva
Module
4.2.2.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 22
W2000108
Single dose oral bioavailability of
tenofovir DF in woodchucks
Truvada
Module
4.2.2.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
D2000076
Single dose oral bioavailability of
tenofovir DF in beagle dogs
Viread
Module
4.2.2.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 29
P2000031
A single dose oral bioavailability
study of tenofovir DF in rhesus
monkeys
Viread
Module
4.2.2.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 30
PC-174-2006
Anti-HBV activity of in vitro
combinations of tenofovir with
nucleoside analogs
Viread
Module
4.2.2.2
Provided in Type II
variation
(EMEA/H/C/419/
II/75)
October 2007
Module 5
Volume 1
TBZZ/93/0025
Protein binding of 524W91 in
human, monkey, mouse and rabbit
plasma (PDM-037)
Emtriva
Module
4.2.2.3
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 25
TOX103
Toxicokinetic study to determine
fetal exposures in CD-1 mice given
TP-0006 orally
Emtriva
Module
4.2.2.3
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 25
CONFIDENTIAL
Page 198
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
TOX103
[Addendum]
Addendum to TOX103:
toxicokinetic study to determine fetal
exposures in CD-1 mice given TP0006 orally
Truvada
Module
4.2.2.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 11
TOX092
[14C]TP-0006: A tissue distribution
and excretion study in rats
Emtriva
Module
4.2.2.3
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 24
P0504-00039.1
Protein binding of cidofovir, cyclic
HPMPC, PMEA and PMPA in
human plasma and serum
Viread
Module
4.2.2.3
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 35
95-DDM1278-002
Determination of distribution of
[14C]-PMPA in male rats following
single administration using whole
body autoradiography
Truvada
Module
4.2.2.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 10
97-DDM4331-001
Tissue distribution of [14C]
GS-4331 in beagle dogs following
oral administration
Viread
Module
4.2.2.3
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 35
96-DDM1278-005
Placental transfer and
pharmacokinetics of PMPA (GS1278) in infant rhesus monkeys
Viread
Module
4.2.2.3
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 35
P2000116
Pharmacokinetics of tenofovir in
healthy adult female lactating rhesus
monkeys following a single 30
mg/kg subcutaneous dose of
tenofovir
Viread
Module
4.2.2.3
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 35
CONFIDENTIAL
Page 199
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Doc #15247
In vitro evaluation of emtricitabine
(FTC) as an inhibitor of human
cytochrome P-450 enzymes and 5’uridine diphosphate glucuronosyl
transferase (UGT) (CTBR Project
No. 48171)
Truvada
Module
4.2.2.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
15396 v1
Identification of the principal human
cytochrome P-450 isoenzyme(s) and
potential glucuronidation responsible
for the metabolism of emtricitabine
(FTC) using pooled human liver
microsomes and bactosomes
containing cDNA-expressed human
cytochrome P-450 (CYP)
isoenzymes
Emtriva
Module
4.2.2.4
Included in
response to CPMP
Day 120 List of
Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume 2
TEIN/93/0015
Metabolic disposition and balance
studies in male CD-1 mice following
oral administration of 120 mg/kg [63
H]524W91 (EXT020)
Emtriva
Module
4.2.2.4
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 24
TOX063
Metabolism and excretion of
[14C]TP-0006 following oral
administration to male cynomolgus
monkeys
Emtriva
Module
4.2.2.4
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes 22-23
TEIN/93/0016
Metabolic disposition of 80 mg/kg
orally administered [6-3H]524W91
in cynomolgus monkeys
Emtriva
Module
4.2.2.4
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 25
CONFIDENTIAL
Page 200
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
14
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
P1278-00008;
96-DDM1278-003
In vitro metabolism of C-PMPA in
human and animal tissues
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 12
P4331-00003;
97-VIT-1278001
In vitro stability of bis-POC PMPA
(GS-4331) in biological fluids
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 12
P433100015.1; 98VIT-4331-001
Epithelial transport and metabolism
of tenofovir disoproxil (Bis-POC
PMPA; GS-4331) in caco-2 cell
monolayers
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 12
V990172-104
The effect of tenofovir and tenofovir
DF on the activities of the
cytochrome P-450 isoforms in
human hepatic microsomes
Truvada
Module
4.2.2.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 3
R2001024
GLP ex-vivo rat cytochrome P-450
induction study following treatment
with tenofovir DF
Truvada
Module
4.2.2.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 12
96-DDM1278-001
Effect of dose on the recovery of
[14C]-PMPA following intravenous
administration to Sprague-Dawley
rats
Viread
Module
4.2.2.5
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 36
CONFIDENTIAL
Page 201
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
Determination of tenofovir
disoproxil and metabolite
concentrations in bile and
gastrointestinal tract, following oral
administration of tenofovir
disoproxil to rats (Gilead Study Nos.
97-DDM-4331-003 and 97-DDM4331-004)
Viread
Module
4.2.2.5
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 36
A pilot study of biliary excretion of
C-PMPA in the beagle dog
Truvada
Module
4.2.2.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 14
PC-104-2018
Effect of HIV protease inhibitors on
MRP4-mediated efflux of tenofovir
Viread
Module
4.2.2.5
Submitted in
response to
Follow-up Measure
(EMEA/H/C/419)
April 2007
Follow-up
Measure
Volume 1
PC-104-2019
In vitro effect of HIV protease
inhibitors on the accumulation of
tenofovir in fresh human kidney
tissue
Viread
Module
4.2.2.5
Submitted in
response to
Follow-up Measure
(EMEA/H/C/419)
June 2008
Follow-up
Measure
Volume 1
PC-103-2001
In vitro interactions of acyclic
nucleoside phosphonate analogs with
human organic cation and anion
transporters
Viread
Module
4.2.2.6
Submitted in
response to
Follow-up Measure
(EMEA/H/C/419)
December
2003
Follow-up
Measure
Volume 1
97-DDM4331-003/4;
P4331-00014
P1278-00011;
96-DDM1278-002
CONFIDENTIAL
14
Page 202
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Available
upon request
Submitted in
Response to
Follow-Up Measure
(EMEA/H/C/419)
June 2005
Follow-up
Measure
Volume 1
Viread
Module
4.2.2.5
Submitted in
Response to
Follow-up Measure
(EMEA/H/C/ 419)
December
2005
Follow-up
Measure
Volume 1
Effect of HIV protease inhibitors and
other therapeutics on the transport of
tenofovir by human renal organic
anion transporter type I (hOAT1)
Viread
Module
4.2.2.6
Provided in Type II
Variation
(EMEA/H/C/419/
II/29)
June 2005
Type II
variation
Volume 1
PC-104-2011
the transport of tenofovir by human
renal organic anion transporter type
3 (hOAT3)
Viread
Module
4.2.2.6
Provided in Type II
Variation
(EMEA/H/C/419/
II29)
June 2005
Type II
variation
Volume 1
PC-104-2014
Lack of contribution from MRP1 in
tubular re-absorption of tenofovir
Viread
Module
4.2.2.6
Submitted in
Response to
Follow-up Measure
(EMEA/H/C/419)
March 2006
Follow-up
Measure
Volume 1
AD-104-2010
the intestinal absorption of tenofovir
disoproxil fumarate in vitro
Viread
Module
4.2.2.5
Submitted in
Response to
Follow-up Measure
(EMEA/H/C/419)
September
2010
Follow-up
Measure
Volume 1
Study Title
Product
AD-104-2001
the transport of tenofovir by the
multidrug resistance related proteins
2 and 4
Viread
AD-104-2002
Lack of contribution from Pglycoprotein (Pgp) in the active
tubular secretion of tenofovir
PC-104-2010
CONFIDENTIAL
Page 203
Volume
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Module
4.2.2.6
Submitted in PSUR
(13 January 2009 to
12 July 2009)
September
2009
Module 5
Volume 1
Viread
Module
4.2.2.6
Previously Not
Submitted
Single-dose iv PK of tenofovir at
two doses in Sprague-Dawley rats
Truvada
Module
4.2.2.7
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 14
P2001025
Intracellular kinetics of 14C – PMPA
in rhesus monkeys
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 14
P2000117
Pharmacokinetics of tenofovir in
healthy and infected rhesus monkeys
administered chronic subcutaneous
doses of tenofovir
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 15
R2000065
Comparison of plasma
pharmacokinetics in rats of tenofovir
following oral administration of
GS-7340-02 or tenofovir DF as
either a suspension in CMC or a
solution in citric acid
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 15
TTEP/93/0020
An acute oral toxicity study in the
mouse with 524W91
Emtriva
Module
4.2.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 1
Study Title
Product
PC-177-2001
The triple combination of tenofovir,
emtricitabine and efavirenz shows
synergistic anti-HIV-1 activity in
vitro: a mechanism of action study
Atripla
PC-180-2018
Effect of increasing multiplicity of
infection on the EC50 of GS-9131
and GS-9148
R2000075
CONFIDENTIAL
Page 204
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TTEP/93/0023
An acute intravenous toxicity study
in the mouse with 524W91
Emtriva
Module
4.2.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 1
TTEP/93/0021
An acute oral toxicity study in the rat
with 524W91
Emtriva
Module
4.2.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 1
TTEP/93/0024
An acute intravenous toxicity study
in the rat with 524W91
Emtriva
Module
4.2.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 1
R990200
An acute oral gavage toxicity study
of tenofovir DF (GS-4331-05) in the
albino rat followed by a 14-day
observation period (ClinTrials
BioResearch Ltd Report No. 89285)
Viread
Module
4.2.3.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 1
D990201
An acute oral gavage toxicity study
of tenofovir DF (GS-4331-05) in the
beagle dog followed by a 14-day
observation period (ClinTrials
BioResearch Ltd Report No. 89286)
Viread
Module
4.2.3.1
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 1
IUW00701
Fourteen-day oral (Gavage) toxicity
study in mice given FTC
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 30
TOX599
A 30-day oral toxicity study in mice
given 524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes 3-4
TOX599
[Addendum]
Addendum - A 30-day oral toxicity
study in mice given 524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 4
CONFIDENTIAL
Page 205
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TOX022
(IUW01001)
Toxicokinetic report for a 6-month
oral (gavage) toxicity study in mice
given FTC with a 3-month interim
kill
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes 5-6
TOX022
[Addendum]
Toxicokinetic report for a 6-month
oral (gavage) toxicity study in mice
given FTC with a 3-month interim
kill
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 32
TOX628
A 6-month oral toxicity study (with a
3-month interim sacrifice) in mice
given 524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes 7-9
TOX097
A 3-month oral gavage study for
bioassay dose selection in CD rats
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
9-10
TOX600
A 30-day oral toxicity study in
cynomolgus monkeys given 524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
11-12
TOX600
Addendum - A 30-day oral toxicity
study in cynomolgus monkeys given
524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 12
TOX627
A 3-month oral toxicity study in
cynomolgus monkeys given 524W91
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
12-13
TOX032
52-week oral toxicity study with
TP-006 in cynomolgus monkeys
with a 4-week recovery period
Emtriva
Module
4.2.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
13-14
CONFIDENTIAL
Page 206
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
M990191
A 14-day repeat dose oral toxicity
study of tenofovir DF in ICR CD-1®
mice
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 17
M990203
(T433100017.1)
A 13-week oral gavage toxicity
study of tenofovir disoproxil
fumarate (Tenofovir DF) in the
albino mouse
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volumes 2-3
M990203-PK
A 13-week oral gavage toxicity
study of tenofovir disoproxil
fumarate (tenofovir DF) in the albino
mouse (Gilead Study #M990203)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 30
96-TOX-4331002
5-day repeated dose oral toxicity
study of GS-4331-02 in male
Sprague-Dawley rats
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 18
98-TOX-4331004
A 14-day oral gavage toxicity study
of bis-POC PMPA fumarate
(GS-4331-05; PMPA prodrug) in the
albino rat
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 18
98-TOX-4331004-PK
Toxicokinetic report for a 14-day
oral gavage toxicity study of bisPOC PMPA fumarate [GS-433105; PMPA prodrug] in the albino rat
(98-TOX-4331-004)
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 18
CONFIDENTIAL
Page 207
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
96-TOX-4331003 (T433100003.2)
of GS-4331-05 in the albino rat
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 7
96-TOX-4331003-PK
(P4331-00004)
Pharmacokinetics of tenofovir
following oral gavage of tenofovir
DF in a 28-day toxicity study in
albino rats (A report on the analysis
of plasma concentration data from
Toxicity Study #96-TOX-4331-003)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 32
97-TOX-4331002
A 13- and 42-week oral gavage
toxicity study (with a 13-week
recovery period) of BIS-POC PMPA
(GS-4331-05) in the albino rat
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volumes
8-12
97-TOX-4331002-PK
Pharmacokinetics of tenofovir in a
13 and 42-week oral gavage Toxicity
study (with a 13-week recovery
period) of tenofovir DF (GS-433105) in rats (A report on the analysis
of plasma concentration in data from
toxicity study #97-TOX-4331-002)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 33
96-TOX-4331001
5-day repeated oral dose toxicity
study with GS-4331 in dogs
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 25
CONFIDENTIAL
Page 208
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
96-TOX-4331001-PK
pilot five day oral toxicity study of
tenofovir DC (GS-4331-02) in
beagle dogs (Toxicity Study #96TOX-4331-001)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 33
96-TOX-4331004 (T433100004.2)
of GS-4331-05 in the beagle dog
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 14
96-TOX-4331004-PK
(P4331-00005)
DF in a 28-day repeat dose toxicity
study in beagle dogs (Gilead
Sciences Study #96-TOX-4331-004PK)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 33
98-TOX-4331003
of GS-4331-05 (bis-POC PMPA;
PMPA Prodrug) in the beagle dog
Truvada
Available
upon request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 26
98-TOX-4331003-PK
28-day repeated dose oral gavage
toxicity study of tenofovir DF in
beagle dogs (A report on analysis of
data from toxicity study 98-TOX4331-003)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 33
CONFIDENTIAL
Page 209
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Study Title
Product
97-TOX-4331001
A 13- and 42-week oral gavage
toxicity study (with a 13-week
recovery period) of Bis-POC PMPA
(GS-4331-05) in the beagle dog
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volumes
15-17
97-TOX-4331001-PK
(P4331-00006)
DF in a 13- and 42-week repeat dose
toxicity study in beagle dogs (A
report on analysis of plasma
concentration data from toxicity
study #97-TOX-4331-001)
Viread
Module
4.2.3.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 34
TX-164-2001
comparing non-degraded and
degraded TDF/FTC in SpragueDawley rats
Truvada
Module
4.2.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volumes 4-5
TX-164-2004
4-week oral gavage toxicity and
toxicokinetic study with
emtricitabine/tenofovir disoproxil
fumarate (FTC/TDF) in male dogs
with a 4-week recovery period
Truvada
Module
4.2.3.2
Provided in Type II
Variation
(EMEA/H/C/594
/II/010)
August 2005
Module 4
Volumes 1-2
18637-0-409R
Mutagenicity test with FTC in the
Salmonella - Escherichia
coli/mammalian-microsome reverse
mutation assay with a confirmatory
assay
Emtriva
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 24
CONFIDENTIAL
Page 210
Volume
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
MUT203
Salmonella/mammalian-microsome
assays with 524W91
Emtriva
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 20
K01-3154
Mutagenicity test of FTC using
microorganisms
Truvada
Module
4.2.3.3.1
Submitted in PSUR
(03 August 2005 to
02 February 2006)
April 2006
PSUR
Volume 2
TOX012
In vitro mammalian cell gene
mutation test (mouse lymphoma
assay)
Emtriva
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 20
96-TOX-4331005
Mutagenicity test with GS-4331-05
in the Salmonella- escherichia coli
mammalian microsome reverse
mutation assay
Viread
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 23
97-TOX-1278003
Mutagenicity test with GS-1278
(PMPA) Lot no. KH01603, GS-1278
(PMPA) Lot No. 1278-B-1, GS4331-05 (PMPA prodrug, bis-POC
PMPA) Lot no. 4331-05-XA-1 (2nd
crop) in the Salmonella mammalian
reverse mutation assay
Viread
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 23
K01-3037
Mutagenicity test of tenofovir using
microorganisms
Viread
Available
upon request
Provided in 3rd
Annual Risk
Benefit
(EMEA/H/C/419/S/
48)
February 2005
3rd Annual
Risk Benefit
Volume 2
CONFIDENTIAL
Page 211
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
97-TOX-4331007
Mutagenicity test on GS-4331-05 in
the L5178Y/TK+/- mouse lymphoma
forward mutation assay
Viread
Module
4.2.3.3.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 23
TX-164-2002
Bacterial reverse mutation assay
with emtricitabine/tenofovir
disoproxil fumarate
Truvada
Available
upon request
Submitted in
Response to
Follow-up Measure
(EMEA/H/C/594)
March 2005
Follow-up
Measure
Volume 1
TX-164-2003
In vitro mammalian cell gene
mutation test (L5178Y/TK+/- mouse
lymphoma assay) with
emtricitabine/tenofovir disoproxil
fumarate
Truvada
Module
4.2.3.3.1
Submitted in
Response to
Follow-up Measure
(EMEA/H/C/594)
March 2005
Follow-up
Measure
Volume 1
TOX011
In vivo mammalian erythrocyte
micronucleus assay
Emtriva
Module
4.2.3.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 20
97-TOX-4331008
Mutagenicity test on GS-4331-05 in
the in vivo mouse micronucleus
assay
Viread
Module
4.2.2.1 &
Module
4.2.3.3.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 23
97-TOX-4331008-PK
Tenofovir levels in mouse plasma:
pharmacokinetics from a single dose
micronucleus study in mice
(97-TOX-4331-008)
Viread
Module
4.2.3.3.2
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 28
CONFIDENTIAL
Page 212
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
23291-0494OECD
In vivo/in vitro unscheduled DNA
synthesis in rat primary hepatocyte
cultures at two time points
Viread
Module
4.2.3.3.2
Submitted in
Response to
Specific Obligation
(EMEA/H/C/ 419)
February 2002
Specific
Obligation
Volume 1
TOX109
Two-year oral oncogenicity study in
CD-1 mice
Emtriva
Module
4.2.3.4.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 20
TOX108
TP-0006: two-year oral oncogenicity
study in CD rats
Emtriva
Module
4.2.3.4.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 20
M990205
An oral carcinogenicity study of
(tenofovir DF) in the albino mouse
Viread
Module
4.2.3.4.1
Provided in Type II
Variation
(EMEA/H/C/419
/II/32
September
2003
Type II
variation
Volumes 110
R990204
An oral carcinogenicity study of
(tenofovir DF) in the albino rat
Viread
Module
4.2.3.4.1
Submitted in
Response to
Specific Obligation
(EMEA/H/C/ 419)
March 2003
Specific
Obligation
Volumes 1-8
TOX036
Study of fertility and early
embryonic development of TP-0006
administered by gavage to CD-1
mice (segment 1)
Emtriva
Module
4.2.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 15
TTEP/95/0028
A fertility study in male rats given
524W91 by gavage
Emtriva
Module
4.2.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 15
CONFIDENTIAL
Page 213
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
98-TOX-4331006
Oral (gavage) fertility and general
reproduction toxicity study of GS4331-05 (bis-POC PMPA) in
Sprague-Dawley rats
Viread
Module
4.2.3.5.1
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 19
TOX033
A dose range-finding study of the
effects of TP-0006 on embryo/fetal
development in mice
Truvada
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 85
TOX037
A study of the effects of TP-0006
(FTC) on embryo/fetal development
in mice
Emtriva
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
16-17
TOX037
Addendum to document No:
TOX037
Truvada
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 85
TOX034
A dose range-finding study of the
effects of TP-0006 on embryo/fetal
development in rabbits
Truvada
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 85
TOX038
A study of the effects of TP-0006 on
embryo/fetal development in rabbits
Emtriva
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volumes
18-19
TOX038
[Addendum]
Addendum to TOX038: A study of
the effects of TP-0006 on
embryo/fetal development in rabbits
Truvada
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 86
97-TOX-4331004
Oral (gavage) developmental toxicity
study of GS-4331-005 in rats
Viread
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 20
CONFIDENTIAL
Page 214
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
98-TOX-4331005
Oral (stomach tube) developmental
toxicity study of GS-4331-05 in
rabbits
Viread
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/ 419)
May 2001
Part III
Volume 22
98-TOX-4331005-PK
Pharmacokinetics of tenofovir in an
oral (stomach tube) developmental
toxicity study of GS-4331-05 (bisPOC PMPA) in rabbits (A report on
analysis of data from toxicity study
98-TOX-4331-005)
Truvada
Module
4.2.3.5.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 85
TOX039
Pre- and postnatal development
study in CD-1 mice given TP-0006
by gavage (segment III)
Emtriva
Module
4.2.3.5.3
Original MAA
(EMEA/H/C/533)
December
2002
Part III
Volume 19
R990202
Oral (gavage) developmental and
perinatal/postnatal reproduction
toxicity study of GS-4331-05 (bisPOC PMPA) in rats including a
postnatal behavioural / functional
evaluation
Viread
Module
4.2.3.5.3
Provided in Type II
Variation
(EMEA/H/C/419/
II/10)
August 2002
Type II
variation
Volumes 1-2
R990202-PK
Tenofovir (GS-1278) plasma
toxicokinetics from a developmental
and perinatal/postnatal reproduction
toxicity study of tenofovir DF in
female rats
Viread
Module
4.2.3.5.3
Provided in Type II
Variation
(EMEA/H/C/419
/II/10)
August 2002
Type II
variation
Volume 2
B990165
A primary eye irritation study in
rabbits with tenofovir DF
(GS-4331-05)
Truvada
Module
4.2.3.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
CONFIDENTIAL
Page 215
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
B990166
A primary skin irritation study in
rabbits with tenofovir DF
(GS-4331-05)
Truvada
Module
4.2.3.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
G990167
A dermal sensitization study in
guinea pigs with tenofovir DF
(GS-4331-05) - modified Buehler
design
Truvada
Module 4.2.
3.7.1
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
TOX146
TP-0006 28-day oral (gavage)
immunotoxicity study in rats.
Truvada
Module
4.2.3.7.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 27
R2000096
A 28-day oral repeat dose study to
evaluate the toxicity of adefovir
dipivoxil (GS-0840), tenofovir DF
(GS-4331-05), or adefovir dipivoxil
in combination with tenofovir DF in
male Sprague-Dawley rats
Viread
Module
4.2.3.7.3
Submitted in
Response to
Specific Obligation
(EMEA/H/C/419)
January 2002
Specific
Obligation
Volume 1
W2000042
A 90-day repeat dose oral toxicity
study of tenofovir DF in woodchucks
Viread
Module
4.2.3.7.3
Submitted in
Response to
Specific Obligation
(EMEA/H/C/ 419)
January 2002
Specific
Obligation
Volume 4
W2000042-PK
Toxicokinetics of tenofovir
following daily oral administration
of tenofovir DF to male and female
woodchucks for 90 days
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 91
V2000122
Human osteoblast calcium
deposition in vitro
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
CONFIDENTIAL
Page 216
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
R2000095
A 3-day oral repeat dose study to
evaluate serum and urine phosphorus
levels in tenofovir DF (GS-433105)-treated male Sprague-Dawley
rats supplemented, following the
final dose, with intraperitoneal or
oral phosphate
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
R2000099
A 3-day oral or intravenous repeat
dose study to evaluate serum and
urine phosphate concentrations in
male Sprague-Dawley rats treated
with tenofovir (GS-1278) or
tenofovir DF (GS-4331-05) and
supplemented with oral phosphate
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
R2000043
A 6-day repeat dose oral exploratory
study of tenofovir DF in male
Sprague-Dawley rats
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 89
R2000036
A 28-day study to evaluate the
effects of tenofovir disoproxil
fumarate (tenofovir DF) on bone
following daily administration by
gavage in the Sprague-Dawley rat
Truvada
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 90
CONFIDENTIAL
Page 217
18AUG2010
Final
Nonclinical
Report
Number
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
Study Title
Product
R2000036-PK
A 28-day study to evaluate the effect
of tenofovir disoproxil fumarate
(tenofovir DF) on bone following
daily administration by gavage in the
Sprague-Dawley rat
Viread
Module
4.2.3.7.3
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 32
P2000078
A 56-day study of tenofovir DF
administered orally and of PMPA
administered by subcutaneous
injection to rhesus monkeys
Viread
Module
4.2.3.7.3
Submitted in
Response to
Specific Obligation
(EMEA/H/C/ 419)
January 2002
Specific
Obligation
Volume 2
P2000078-PK
Toxicokinetics of tenofovir DF
administered orally and tenofovir
administered by subcutaneous
injection to rhesus monkeys for 56days
Viread
Module
4.2.3.7.3
Provided in Type II
Variation
(EMEA/H/C/419/
II/10)
August 2002
Type II
variation
Volume 1
TOX 153
A 1-month mouse oral qualification
study of TP-0006 and TP-0296
(degradant)
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volumes 9596
TX-162-2001
A 1-month oral qualification study of
TP-0006 produced by the menthol
process in CD-1 mice
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volumes 9798
TOX151
Bacterial reverse mutation assay of
TP-0006 to qualify degradant TP0296
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 95
CONFIDENTIAL
Page 218
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
TOX152
In vitro mammalian chromosome
aberration study of TP-0006 to
qualify degradant TP-0296
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 95
R2000081
14-day oral toxicity study comparing
tenofovir DF and degraded tenofovir
DF in Sprague-Dawley rats
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 93
R2000081-PK
14-day oral toxicity study comparing
tenofovir DF and degraded tenofovir
DF in Sprague-Dawley rats
Truvada
Module
4.2.3.7.6
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volumes 3094
Safepharm
Laboratories
1432/009
28-day repeated dose oral (gavage)
toxicity study in the rat
Truvada
Available
Upon
Request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 99
Safepharm
Laboratories
1432/021
28-day repeated dose oral (gavage)
toxicity study in the rat
Truvada
Available
Upon
Request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 99
Safepharm
Laboratories
1432/022
CMIC: Reverse mutation assay
“Ames Test” using Salmonella
typhimurium and Eschericha coli
Truvada
Available
Upon
Request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 98
Safepharm
Laboratories
1432/023
CMIC: L5178Y/TK+/- mutation
assay
Truvada
Available
Upon
Request
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 99
CONFIDENTIAL
Page 219
18AUG2010
Final
Nonclinical
Report
Number
Study Title
Product
Location
within FDC
MAA
EU Procedure
(& number)
Date
Submitted
Dossier
Number/Type
Volume
95-TOX-1278006
Mutagenicity test with GS-1278
(PMPA) lot #1016-56-26 in the
Salmonella-Escherrichia coli
mammalian-microsome reverse
mutation assay
Truvada
Module
4.2.3.7.7
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 98
95-TOX-1278007
Mutagenicity test on GS-1278
(PMPA) in the L5178Y/TK+/mouse lymphoma forward mutation
assay
Truvada
Module
4.2.3.7.7
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 98
T1278-00034
PMPA in SIV-infected and
uninfected rhesus macaques: studies
from Martin and Tsai Laboratories.
Viread
Available
upon request
Original MAA
(EMEA/H/C/419)
May 2001
Part III
Volume 26
T1278-00030
The effects of PMPA treatment on
cortical bone strength in rhesus
monkeys (Macaca mulatta).Thesis,
University of California, Davis
Truvada
Module
4.2.3.7.7
Original MAA
(EMEA/H/C/594)
March 2004
Module 4
Volume 98
CONFIDENTIAL
Page 220
18AUG2010
Table 32.
Final
Gilead Clinical Reports
Cross-reference to Study Report
Clinical Study
Number
Study Title
Product
FTC-110
A study to evaluate the relative and
absolute bioavailability of emtricitabine
in healthy volunteers
Emtriva
Module 5.3.1.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
1–4
FTC-109
A pilot study to evaluate the
bioavailability/bioequivalence between
the 100 mg and 200 mg capsule
formulations of emtricitabine in healthy
volunteers.
Emtriva
Module 5.3.1.2
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
5-6
FTC-111
An open-label study to compare the
bioavailability/bioequivalence of two
dosage forms of emtricitabine (100 mg
capsules and 200 mg capsules) and the
effect of food on the bioavailability of
emtricitabine administered as a 200 mg
capsule in healthy volunteers.
Emtriva
Module 5.3.1.2
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
7–9
FTC-112
An open-label study to determine the
bioequivalence between Epivir tablets
and encapsulated Epivir tablets in
healthy volunteers.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
54-55
FTC-113
An open-label study to determine the
bioequivalence between Zerit
capsules and over-encapsulated Zerit
capsules in healthy volunteers.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
16-18
CONFIDENTIAL
Page 221
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Location within
FDC MAA
Volume
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
GS-US-162-0101
A phase 1, open-label, randomized,
three-way crossover study to evaluate
the effect of food on the bioavailability
of emtricitabine administered as
Emtriva oral solution in healthy
volunteers.
Emtriva
Available upon
request
Submitted in
Response to
Follow-Up
Measure
(EMEA/H/C/ 533)
June 2004
Follow-Up
Measure
Volume 1
GS-00-914
A phase 1, randomized, open label,
pharmacokinetic study in healthy
volunteers to assess the 1)
bioequivalence of the clinical and
intended commercial formulations of
tenofovir disoproxil fumarate and the
2) effect of food on the bioavailability
and pharmacokinetics of the intended
commercial formulation of tenofovir
disoproxil fumarate 300 mg tablets.
Viread
Module 5.3.1.2
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volume 8
GS-US-104-0172
A phase 1 pharmacokinetic study in
healthy volunteers to evaluate the
bioequivalence of the combined
formulated tablet of tenofovir
disoproxil fumarate and emtricitabine
compared to tenofovir disoproxil
fumarate and emtricitabine
administered concurrently and the
effect of food on pharmacokinetics.
Truvada
Module 5.3.1.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
19
CONFIDENTIAL
Page 222
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
P1278-00030
Validation of an HPLC
chromatographic method for the
quantitation of PMPA (GS-1278) in
human serum (Harris Laboratories
Project 18758_1.01)
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
20
P1278-00031
Validation of a high performance liquid
chromatographic mass spectrometric
method for the determination of GS1278 (R-PMPA) in human urine
(Phoenix Project 001324NRO).
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
20
P1278-00032
Validation of a high performance liquid
chromatographic mass spectrometric
method for the determination of GS1278 (R-PMPA) in human serum
(Phoenix Project 993679NHC).
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
21
P1278-00033
Validation of a liquid chromatographic
method for the quantitation of PMPA
in urine (Harris Laboratories Project
18758_2.01). November 1996,
amended December 1996, April 1997,
January 1999 and July 1999
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
21
20143v3
Validation of a Method for the
Determination of Emtricitabine and
Tenofovir in Human Plasma by
LC-MS/MS.
Truvada
Module 5.3.1.4
Previously not
submitted.
CONFIDENTIAL
Page 223
18AUG2010
Final
Clinical Study
Number
Study Title
Product
FTC-106
An evaluation of the absorption,
distribution, metabolism and excretion
(ADME) of C14 labelled emtricitabine
(FTC) in healthy male volunteers.
Emtriva
Module 5.3.3.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
17–20
143-001
A phase 1, randomized, single-dose
placebo-controlled trial to evaluate the
safety and pharmacokinetics of
524W91 (Emtricitabine).
Truvada
Module 5.3.3.2
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
27
FTC-116
A study to evaluate the
pharmacokinetics of emtricitabine
following multiple-dose administration
in HIV-exposed neonates receiving
prophylactic zidovudine therapy for
perinatal HIV transmission.
Emtriva
Available upon
request
Submitted in
response to
Follow-Up
Measure
(EMEA/H/C/533)
June 2006
Follow-up
Measure
Volume 1
FTC-101
Phenotypic and genotypic analysis of
recombinant HIV-1 clinical isolates.
Emtriva
Module 5.3.1.2
Original MAA
(EMEA/H/C/ 533)
December
2002
Module 5
Volumes
22-27
FTC-101
A dose-escalation study to investigate
the safety, tolerance, pharmacokinetics
and antiviral activity of multiple repeat
doses of emtricitabine in patients who
are infected with HIV-1.
Emtriva
Module 5.3.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
22–27
CONFIDENTIAL
Page 224
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Location within
FDC MAA
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
FTC-102
A Randomized, Comparative Trial of
FTC Administered Once-Daily vs 3TC
Administered Twice-Daily to HIV-1
Infected Subjects in a 10-day Dosing
Regimen
Emtriva
Module 5.3.3.2
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
28-31
FTC-105
An evaluation of the safety and
pharmacokinetics of single, escalating
oral doses of emtricitabine (FTC) in
HIV-1 infected or exposed paediatric
patients aged < 18 years old.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
32-38
FTC-107
An evaluation of the pharmacokinetics
of emtricitabine in volunteers with
varying degrees of renal impairment.
Emtriva
Module 5.3.3.3
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
39–43
FTC-107
Investigation of the use of dosing
interval as a means of normalizing
emtricitabine exposure in patients with
varying degrees of renal impairment
(Analyses and simulations based on
data for study FTC-107).
Emtriva
Module 5.3.3.3
Included in
Response to
CHMP Day 120
List of Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume 2
13542v1
Statistical analysis of emtricitabine
pharmacokinetic parameter estimates
vs. demographic variables in adult
healthy and HIV infected populations
evaluated in emtricitabine HIV clinical
program.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
73
CONFIDENTIAL
Page 225
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Location within
FDC MAA
Volume
18AUG2010
Final
Clinical Study
Number
Product
GS-01-919
A phase 1, open-label, parallel-group
study to evaluate the pharmacokinetics
of tenofovir disoproxil fumarate in
subjects with normal and impaired
renal function.
Viread
Module 5.3.3.3
Provided in Type II
variation
(EMEA/H/C/419/
II/09)
August 2002
Type II
Variation
Volumes
1–2
GS-01-931 A/B
A phase 1 open-label, parallel-group,
single-dose study to evaluate the
pharmacokinetics of tenofovir DF in
subjects with normal and impaired
hepatic function.
Viread
Module 5.3.3.3
Provided in Type II
variation
(EMEA/H/C/419
II/030)
July 2003
Module 5
Volumes
1–2
GS-01-926
A Phase I Study of Tenofovir
Disoproxil Fumarate (PMPA Prodrug),
a Novel Nucleotide Analog Reverse
Transcriptase Inhibitor, in Children
with HIV Infection
Viread
Available upon
request
Submitted in
response to a
Follow-Up
Measure
(EMEA/H/C/419)
March 2006
Follow-up
Measure
Volumes
1–6
GS-01-927
A Phase 1í2, Open-Label, DoseFinding, Multiple Center Study of the
Pharmacokinetics and Safety of
Tenofovir Disoproxil Fumarate
Administered in Combination with
Other Antiretroviral Agents as
Advanced Therapy in HIV-1 Infected
Children and Adolescents (Aged 4í17)
Viread
Available upon
request
Submitted in
response to a
Follow-Up
Measure
(EMEA/H/C/ 419)
September
2005
Follow-up
Measure
Volumes
1–3
Page 226
Date
Submitted
Volume
Study Title
CONFIDENTIAL
EU Procedure (&
number)
Dossier
Number/
Type
Location within
FDC MAA
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
GS-02-983
A phase 1, open-label, single-dose,
single center study of the
pharmacokinetics of tenofovir
disoproxil fumarate oral suspension
administered in combination with other
antiretroviral agents in HIV-1 infected
children.
Viread
Available upon
request
Submitted in
response to
Follow-up Measure
(EMEA/H/C/419)
November
2005
Follow-up
Measure
Volume 1
GS-US-104-0235
Open-Label, Single-Group, 48-Week,
Phase 4 Study to Evaluate the Safety
And Tolerability of Tenofovir DF in
Combination With Emtricitabine in
Treatment-Naïve or
Treatment-Experienced HIV1Infected Patients With Varying
Degrees of Renal Impairment.
Truvada
Module 5.3.3.3
Submitted in
response to
Follow-Up
Measure
(EMEA/H/C/594)
April 2007
Follow-up
Measure
Volumes
16
FTC-103
An open-label study to evaluate
pharmacokinetic interactions of
emtricitabine, Retrovir and Zerit in
healthy male and female volunteers.
Emtriva
Module 5.3.3.4
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
44–46
FTC-104
A study to evaluate the potential
pharmacokinetic interactions of
emtricitabine with indinavir and MKC442 (emivirine).
Emtriva
Module 5.3.3.4
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
47–50
CONFIDENTIAL
Page 227
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
FTC-108
An open-label, randomized crossover
study to evaluate the pharmacokinetics
of emtricitabine and famciclovir
administered alone or in combination in
healthy volunteers.
Emtriva
Module 5.3.3.4
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
51–55
FTC-115
An open label, randomized, three way
crossover study to evaluate the steadystate pharmacokinetics of emtricitabine
and zidovudine when administered
alone and in combination in healthy
volunteers.
Truvada
Module 5.3.3.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
72
FTC-114
An open-label, randomised, three-way
crossover study to evaluate the steadystate pharmacokinetics of emtricitabine
and tenofovir disoproxil fumarate when
administered alone and in combination
in healthy volunteers.
Truvada
Module 5.3.3.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
73
GS-01-932
A phase 1, open-label, drug-drug
interaction study to assess the
disoproxil fumarate and enteric-coated
didanosine capsules in healthy
volunteers.
Viread
Module 5.3.3.4
Submitted in
response to
Follow-Up
Measure from the
original Letter of
Undertaking
(EMEA/H/C/419)
June 2002
Follow-up
Measure
Volumes
1–2
CONFIDENTIAL
Page 228
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Location within
FDC MAA
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
GS-02-984
A phase 1, open label, drug-drug
interaction study to assess the
disoproxil fumarate, dose reduced
didanosine delayed release capsules
and abacavir sulfate in healthy
volunteers.
Viread
Module 5.3.3.4
Provided in Type II
variation
(EMEA/H/C/419/
II/18)
February
2003
Type II
Variation
Volume 1
GS-01-943
A phase 1, randomised, open label
multi-dose, drug interaction study to
assess the pharmacokinetics of
tenofovir disoproxil fumarate and
lopinavir/ritonavir under fed conditions
in healthy volunteers.
Viread
Module 5.3.3.4
Submitted in
response to
Follow-Up
Measure from the
revised Letter of
Undertaking
(EMEA/H/C/419)
March 2003
Follow-up
Measure
Volumes
1–2
GS-01-930
A phase 1, open label, drug interaction
study evaluating the effect of tenofovir
disoproxil fumarate on the
pharmacokinetics of
norgestimate/ethinyl estradiol in
healthy females.
Truvada
Module 5.3.3.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
56-57
GS-01-929
A phase 1, open label study evaluating
the effect of tenofovir disoproxil
fumarate on methadone
pharmacokinetics in opiate-maintained
subjects.
Truvada
Module 5.3.3.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
54-55
CONFIDENTIAL
Page 229
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
Location within
FDC MAA
GS-01-940
A phase 1, open-label, drug interaction
study to assess the pharmacokinetic and
drug interaction potential between
tenofovir disoproxil fumarate (TDF)
and adefovir dipivoxil (ADV) in
healthy volunteers.
Truvada
Module 5.3.3.4
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
58
GS-02-1037
A phase 1, open-label, drug interaction
study to assess the pharmacokinetics of
tenofovir disoproxil fumarate and
ribavirin in healthy volunteers.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
59
GS-02-1038
A Phase 1, Open-Label, Study on
Pharmacokinetic Interaction between
Tenofovir DF and Rifampin in Healthy
Subjects
Truvada
Module 5.3.3.4
Provided in Type II
variation
(EMEA/H/C/594/
II/025)
November
2006
Type II
Variation
Volume 1
GS-US-104-0236
A Phase 1, Open-Label, Single- and
Multiple-Dose, Drug-Drug Interaction
Study to Assess the Pharmacokinetics
of Tenofovir Disoproxil Fumarate and
Unboosted and Ritonavir-Boosted
Saquinavir Mesylate in Healthy
Volunteers
Truvada
Module 5.3.3.4
Provided in a Type
II variation
(EMEA/H/C/594/
II/011)
October
2005
Type II
Variation
Volume 1
CONFIDENTIAL
Page 230
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Truvada
Module 5.3.3.4
Provided in a Type
II variation
(EMEA/H/C/594
/II/011)
October
2005
Type II
Variation
Volume 1
Volume
GS-US-104-0237
A Phase 1, Randomized, Open-Label,
Multi-Dose, Safety and
Pharmacokinetic Drug Interaction
Study of Tenofovir Disoproxil
Fumarate and Nelfinavir Mesylate in
Healthy Subjects
GS-00-909
A phase 1, randomized, open-label,
multiple-dose, drug interaction study to
assess the pharmacokinetics of
tenofovir disoproxil fumarate (TDF),
lamivudine (3TC), didanosine (ddI),
indinavir (IDV), ABT-378/ ritonavir
and efavirenz (EFV) in healthy
volunteers.
Viread
Module 5.3.3.4
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
5–7
GS-US-174-0105
A Open-label, Randomized, three-way,
Crossover Study to Evaluate the
potential for and extent of
Pharmacokinetic Interactions Between
the Combination of Emtricitabine and
Tenofovir Disoproxil Fumarate and
Tacrolimus when administered alone
and together in Health Volunteers.
Truvada
Module 5.3.3.4
Submitted with
PSUR
(03 August 2006 to
02 February 2007)
March 2007
PSUR
Volume 2
CONFIDENTIAL
Page 231
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
TDF-06-063
(Gilead
Submission
Reference)
Renal Impairment Data Summary
Viread
Module 5.3.3.5
Provided
subsequent to the
Updated
Cumulative
Review of Renal
Events submitted
in response to the
CHMP Assessment
Report of the
PSUR
(01 November
2004 to 30 April
2005)
(EMEA/H/C/419)
April 2006
Data
Summary
Volume 1
GS-96-701
A phase 1-2, randomized, double-blind,
placebo-controlled study of the safety,
tolerance, pharmacokinetics, and
antiviral activity of 9-[(R)-2(phosphonomethoxy)propyl]adenine
(PMPA) in HIV infected patients.
Viread
Module 5.3.4
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
1-2
GS-97-901
A Phase 1-2 randomized, double-blind,
placebo-controlled study of the safety,
tolerance, pharmacokinetics, and
antiviral activity of tenofovir disoproxil
fumarate in HIV-infected patients.
Viread
Module 5.3.4
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
2-3
CONFIDENTIAL
Page 232
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
FTC-301A
A randomized, double-blind,
equivalence trial comparing
emtricitabine to stavudine within a
triple drug combination containing
didanosine plus efavirenz in
antiretroviral-drug naïve HIV-1
infected patients. (24 week clinical
study report [with 319 evaluable
patients at week 48])
Emtriva
Module 5.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
57-66
FTC-301A
A randomized, double-blind,
emtricitabine to stavudine within a
triple drug combination containing
didanosine plus efavirenz in
antiretroviral-drug naïve HIV-1
infected patients. (Final 48 week
clinical/statistical report [with 571
evaluable patients at Week 48])
Emtriva
Module 5.3.5.1
Included in
Response to
CHMP Day 120
List of Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume
10
FTC-302
A randomized, double-blind
emtricitabine to lamivudine within a
triple combination in antiretroviraldrug naïve HIV 1 infected patients.
Emtriva
Module 5.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
67–74
CONFIDENTIAL
Page 233
18AUG2010
Final
Clinical Study
Number
Study Title
Product
FTC-303 (PK
substudy)
A randomized, open-label equivalence
study of FTC vs. lamivudine in patients
on a stable triple antiretroviral therapy
regimen containing lamivudine,
stavudine or zidovudine, and a protease
inhibitor or non-nucleoside reverse
transcriptase inhibitor.
Emtriva
Module 5.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
75–80
FTC-303
A randomized, open-label equivalence
study of FTC vs. lamivudine in patients
on a stable triple antiretroviral therapy
regimen containing lamivudine,
stavudine or zidovudine, and a protease
inhibitor or nonnucleoside reverse
transcriptase inhibitor.
Emtriva
Module 5.3.5.1
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volumes
75–80
FTC-303
Phenotypic analysis of recombinant
HIV-1 clinical isolates.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
153
FTC-303
Addendum to clinical/statistical report
(ie TLOVR analysis)
Emtriva
Module 5.3.5.1
Included in
response to CHMP
Day 120 List of
Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume 1
FTC-303
Addendum 2 – Medical narrative for all
patients who discontinued for any
reason.
Truvada
Available upon
request
Included in
response to CHMP
Day 120 List of
Questions
(EMEA/H/C/594)
September
2004
Response to
Questions
Volume 6
CONFIDENTIAL
Page 234
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Location within
FDC MAA
Volume
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
FTC-303
Incidence of adverse events ( 5%) in
emtricitabine patients coadministered
zidovudine compared with
emtricitabine patients who did not take
zidovudine.
Emtriva
Available upon
request
Included in
Response to
CHMP Day 120
List of Questions
(EMEA/H/C/533)
May 2003
Response to
Questions
Volume 3
FTC-303 (ANRS099/ALIZE)
Randomized Phase 3 study comparing
the efficacy and the tolerance of
maintaining an antiprotease tritherapy
versus changing to a combination of
FTC/ddI/Efavirenz administered once
daily in the treatment of HIV-1 infected
patients with an undetectable viral
load.).
Emtriva
Available upon
request
Original MAA
(EMEA/H/C/533)
December
2002
Module 5
Volume
80
FTC-301
A randomized, open-label superiority
trial comparing emtricitabine to
abacavir within a triple drug
combination in antiretroviral-drug
naïve HIV-1 infected patients.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
154
MKC-401
A randomized, open-label study of
Emivirine combined with Stavudine
and Emtricitabine versus Abacavir
combined with Stavudine and
Emtricitabine in HIV-infected patients
who are treatment naïve.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
156-161
CONFIDENTIAL
Page 235
Volume
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
Location within
FDC MAA
GS-98-902
A phase 2, randomized, double-blind,
placebo-controlled study of the safety
and antiviral activity of the addition of
tenofovir disoproxil fumarate (PMPA
Prodrug) to combination antiretroviral
regimens in treatment-experienced
HIV-infected patients (48 week clinical
study report) Version 2.
Viread
Module 5.3.5.1
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
9–12
GS-98-902
HIV-infected patients (Interim
extension report).
Viread
Module 5.3.5.1
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
13-14
GS-98-902
Genotypic and phenotypic analyses of
HIV-1 from patients in a phase 2 study
of tenofovir disoproxil fumarate for the
treatment of HIV-1 infection (Final 48
week virology study report).
Viread
Module 5.3.5.1
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volume
13
CONFIDENTIAL
Page 236
Volume
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
Study Title
Product
Location within
FDC MAA
GS-98-902
HIV-infected patients (Final clinical
study report).
Viread
Module 5.3.5.1
Submitted in
response to
Specific Obligation
from the Letter of
Undertaking
(EMEA/H/C/419)
January
2002
Specific
Obligation
Volumes
1–3
GS-98-902
Genotypic & phenotypic analyses of
HIV-1 from patients in the 48 week
extension phase of a phase 2 study of
tenofovir disoproxil fumarate for the
treatment of HIV-1 infection. (Final
extension phase virology study report)
Viread
Module 5.3.5.1
Submitted in
response to
Specific Obligation
from the Letter of
Undertaking
(EMEA/H/C/419)
January
2002
Specific
Obligation
Volumes
1–3
GS-99-907
treatment of HIV-1 infection. (Interim
24 week virology study report)
Viread
Module 5.3.5.1
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volume
19
GS-99-907
A phase 3, double-blind, randomized,
placebo-controlled multicenter study of
the safety and efficacy of tenofovir
disoproxil fumarate administered in
combination with other antiretroviral
agents for the treatment of HIV 1
infected patients. (Interim 24 week
clinical study report)
Viread
Module 5.3.5.1
Original MAA
(EMEA/H/C/419)
May 2001
Part IV
Volumes
15–18
CONFIDENTIAL
Page 237
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
Study Title
Product
Location within
FDC MAA
GS-99-907
agents for the treatment of HIV 1
Viread
Module 5.3.5.1
Submitted in
response to
Specific Obligation
from the Letter of
Undertaking
(EMEA/H/C/419)
January
2002
Specific
Obligation
Volumes
1–3
GS-99-907-PK
agents for the treatment of HIV-1
Viread
Module 5.3.5.1
Submitted in
response to
Specific Obligation
from the Letter of
Undertaking
(EMEA/H/C/419)
March 2002
Specific
Obligation
Volumes
1–3
GS-99-907
treatment of HIV-1 infection.
(48 week virology study report)
Viread
Module 5.3.5.1
Submitted in
response to
Specific Obligation
from the Letter of
Undertaking
(EMEA/H/C/419)
April 2002
Specific
Obligation
Volume 1
CONFIDENTIAL
Page 238
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
Study Title
Product
GS-02-1008
(RAVE)
A phase II, open-label, multicentre,
randomised, comparator study of
substitution with tenofovir or abacavir
in HIV̂1 infected individuals, with a
viral load < 50 copies/mL, receiving a
thymidine analogue (zidovudine or
stavudine) as part of their highly active
antiretroviral therapy (HAART)
Viread
Available upon
request
Submitted in PSUR
(01 November
2005 to 30 April
2006)
(EMEA/H/C/419)
June 2006
PSUR
Volume 2
GS-99-903
multicenter study of the treatment of
antiretroviral-naive, HIV 1 infected
patients comparing tenofovir disoproxil
fumarate administered in combination
with lamivudine and efavirenz versus
stavudine, lamivudine, and efavirenz.
(48 week clinical study report)
Viread
Module 5.3.5.1
Provided in Type II
variation
(EMEA/H/C/
419/II/08
August 2002
Part IV
Volumes
1–4
GS-99-903
antiretroviral-naive, HIV 1 infected
(144 week clinical study report)
Viread
Module 5.3.5.1
Provided in Type II
variation
(EMEA/H/C/419/
II/039)
May 2004
Module 5
Volumes
1-6
CONFIDENTIAL
Page 239
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
GS-99-903 (240week clinical study
report)
A open-label extension 96-week
interim study report); A phase 3,
randomized, double-blind, multicenter
study of the treatment of antiretroviralnaive, HIV 1 infected patients
comparing tenofovir disoproxil
Viread
Available upon
request
Submitted in
response to a
Follow-Up
Measure
(EMEA/H/C/419)
August 2006
Follow-up
measure
Volume 1
GS-99-903 (Openlabel extension
phase)
A Phase 3, randomized, double-blind,
antiretroviral-naïve, HIV1 infected
(192-week extension phase).
Viread
Available upon
request
Submitted in
response to a
Follow-Up
Measure
(EMEA/H/C/419)
December
2008
Follow-up
measure
Volume 1
GS-01-934
White paper including 8-16 week
efficacy and safety data in a Phase 3,
randomized, open label, multicenter
study of the treatment of antiretroviralnaïve, HIV-1 infected patients
fumarate and emtricitabine in
combination with efavirenz with
lamivudine and zidovudine in
combination with efavirenz.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
153
CONFIDENTIAL
Page 240
Volume
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
GS-01-934
(Interim 24-week data); A Phase 3,
randomized, open-label, multicenter
study of the treatment of antiretroviralnaive, HIV-1-infected subjects
combination with efavirenz versus
combivir (lamivudine/zidovudine) and
efavirenz.
Truvada
Available upon
request
Submitted in
Response to
CHMP D120 List
of Questions
(EMEA/H/C/594)
September
2004
Response to
Questions
Volume 4
GS-01-934
Multicenter Study of the Treatment of
Antiretroviral-Naive, HIV-1 Infected
Subjects Comparing Tenofovir
Disoproxil Fumarate and Emtricitabine
in Combination with Efavirenz Versus
Combivir (lamivudine/zidovudine) and
Efavirenz (48 Weeks)
Truvada
Module 5.3.5.1
Provided in Type II
variation
(EMEA/H/C/594/
II/03)
June 2005
Type II
Variation
Volumes
1-8
GS-01-934
Efavirenz (96-week data).
Truvada
Available upon
request
Original MAA
(EMEA/H/C/797)
October
2006
Module 5
Volumes
1012
CONFIDENTIAL
Page 241
Volume
18AUG2010
Final
Clinical Study
Number
Product
GS-01-934
Efavirenz (144-week data).
Truvada
Module 5.3.5.1
Included in
Response to
CHMP D180 List
of Outstanding
Issues
(EMEA/H/C/594)
August 2007
Response to
questions
Volumes
212
GS-01-934
(168-week clinical efficacy and safety
summary); A phase 3, randomized,
open-label, multicenter study of the
treatment of antiretroviral-naive, HIV-1
infected subjects comparing tenofovir
disoproxil fumarate and emtricitabine
in combination with efavirenz versus
efavirenz.
Atripla
Available upon
request
Included in
Response to
CHMP D180 List
of Outstanding
Issues
(EMEA/H/C/797)
July 2007
Response to
questions
Volume 1
GS-01-934
(240/288 week data); A phase 3,
randomized, open-label, multicenter
study of the treatment of antiretroviralnaïve, HIV-1 infected subjects
combination with efavirenz versus
efavirenz,
Atripla
Available upon
request
Submitted in
Response to
Follow-Up
Measure
(EMEA/H/C/797)
January
2010
Follow-up
Measure
Volume 1
Page 242
Date
Submitted
Volume
Study Title
CONFIDENTIAL
EU Procedure (&
number)
Dossier
Number/
Type
Location within
FDC MAA
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
Study Title
Product
Location within
FDC MAA
M02-418
(GS-02-982)
(48 week interim report); A
randomized, open-label study of 800
mg lopinavir/200 mg ritonavir QD in
combination with tenofovir DF and
emtricitabine vs. 400 mg lopinavir/100
mg ritonavir BID in combination with
tenofovir DF and emtricitabine in HIVinfected antiretroviral-naïve patients
Viread
Module 5.3.5.1
Submitted in Type
II Variation
(EMEA/H/C/419/
II/29)
December
2004
Type II
Variation
Volumes
1–7
M02-418
(GS-02-982)
(96 week report); A randomized, openlabel study of 800 mg lopinavir/200 mg
ritonavir QD in combination with
tenofovir DF and emtricitabine vs. 400
mg lopinavir/100 mg ritonavir BID in
combination with tenofovir DF and
emtricitabine in HIV-infected
antiretroviral-naïve patients
Viread
Module 5.3.5.1
Submitted in PSUR
(01 May 2005 to
30 October 2005)
December
2005
PSUR
Volume 1
CONFIDENTIAL
Page 243
18AUG2010
Final
Clinical Study
Number
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
June 2009
PSUR
Volume 1
Study Title
Product
Location within
FDC MAA
GS-MC-164-0111
A Phase 3, Open-label, Multi-center,
Randomized, 48 Week Study to
Compare the Effect on Prevention and
Resolution of Treatment Related
Adverse Events of a Simplified, Once
Daily Regimen of a Fixed Dose
Combination Tablet of Emtricitabine
and Tenofovir DF Versus Twice Daily
Co-formulated Zidovudine and
Lamivudine (Combivir®) or
Zidovudine and Lamivudine, in
Virologically Suppressed, HIV Infected
Patients Taking Efavirenz.
Truvada
Module 5.3.5.1
Submitted with
PSUR
(03 April 2008 to
02 April 2009)
GS-ES-164-0154
Pilot phase IV, multicenter,
randomized, open-label and controlled
study to assess the evolution of
peripheral body fat distribution after
switching from AZT containing
backbone to Truvada in HIV-1-infected
patients on HAART (RECOMB Study)
Truvada
Module 5.3.5.1
Previously not
submitted.
CONFIDENTIAL
Page 244
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
Study Title
Product
FTC-202
Final Report; An open-label study to
evaluate the safety, tolerance, antiviral
activity and pharmacokinetics of
emtricitabine in combination with
efavirenz and didanosine in a oncedaily regimen in HIV-infected
antiretroviral therapy naïve or very
limited antiretroviral exposed pediatric
subjects. Analysis Report of Age
Group 1.
Emtriva
Available upon
request
Submitted with
PSUR
(03 April 2001 to
02 April 2010)
May 2010
PSUR
Volume 1
FTC-202
Final Report; An open-label study to
evaluate the safety, tolerance, antiviral
activity and pharmacokinetics of
emtricitabine in combination with
efavirenz and didanosine in a oncedaily regimen in HIV-infected
antiretroviral therapy naïve or very
limited antiretroviral exposed pediatric
subjects. Statistical Report of the Final
Analysis Report Groups 2 & 3 (Ages 312 and 13-21 years).
Emtriva
Available upon
request
Submitted with
PSUR
(03 April 2009 to
02 April 2010)
May 2010
PSUR
Volume 1
FTC-203
An Open-Label Study of a Once Daily
Dose of Emtricitabine in Combination
with Other Antiretroviral Agents in
HIV-Infected Pediatric Subjects
Truvada
Available upon
request
Provided in a Type
II variation
(EMEA/H/C/594/
II/013)
November
2005
Type II
Variation
Volume 1
CONFIDENTIAL
Page 245
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
FTC-203
(Updated 24 week report); An openlabel study of a once daily dose of
emtricitabine in combination with other
antiretroviral agents in HIV-infected
paediatrics.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
162-164
FTC-203
(48 week analysis); An open-label
study of a once daily dose of
emtricitabine in combination with other
antiretroviral agents in HIV-infected
pediatric subjects.
Emtriva
Available upon
request
Provided in a Type
II variation
EMEA/H/C/553/
II/23
April 2005
Type II
Variation
Volumes
1-7
FTC-211
An Open-label Study of a Once-daily
Dose of Emtricitabine in Combination
with Other Antiretroviral Agents in
HIV-infected Pediatric Subjects
Truvada
Available upon
request
Provided in a Type
II variation
(EMEA/H/C/594/
II/013)
November
2005
Type II
Variation
Volume 1
FTC-350
An open-label, extension study of
emtricitabine (Emtriva/FTC) in patients
who are a virologic success and
currently enrolled in FTC-303.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
155
FTC-201
Pilot study evaluating the efficacy and
tolerance of the combination FTC + ddI
+ Efavirenz administered once daily in
the treatment of HIV-1 infected
antiretroviral naïve patients (ANRS
091 - Montana Study).
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
154
CONFIDENTIAL
Page 246
Volume
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
ACTG 5015
A Phase II exploratory study examining
immunologic and virologic indices in
two age-differentiated cohorts of HIVinfected subjects to explore the basis of
accelerated HIV-disease progression
associated with aging.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volume
155
GS-00-917
An open-label study to assess the antiHIV-1 activity of tenofovir disoproxil
fumarate (TDF) in antiretroviral-naive
patients who are chronically infected
with HIV-1.
Truvada
Available upon
request
Submitted in
response to
Specific Obligation
from the revised
Letter of
Undertaking
(EMEA/H/C/594)
March 2006
Specific
Obligation
Volume 1
GS-02-1015 (“3 O
D & opiate
substitution”)
Open-label multicenter study to assess
the efficacy, the tolerability and the
adherence of an once daily (QD) taken
antiretroviral therapy (ART) containing
the NtRTI tenofovir DF 300 mg in
combination with the best suitable once
a day regimen being 1 NRTI plus 1 PI
or 1 NRTI plus 1 NNRTI in HIV-1infected IVDU-patients with opiate
substitution being either antiretroviralnaive or with suppressed viral load and
without a history of virological failure
Viread
Available upon
request
Submitted in PSUR
(01 November
2006 to 31 October
2007)
December
2007
Module 5
Volume 1
CONFIDENTIAL
Page 247
Volume
18AUG2010
Final
Clinical Study
Number
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Study Title
Product
GS-99-908
(Interim clinical
study report)
An open-label, multicenter,
compassionate access study of the
safety of tenofovir disoproxil fumarate
antiretroviral agents for the treatment
of HIV-1 infected patients.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
136-137
GS-99-908 (Final
clinical study
report)
An open-label, multicenter,
compassionate access study of the
safety of tenofovir disoproxil fumarate
antiretroviral agents for the treatment
of HIV-1 infected patients.
Truvada
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Volumes
138-139
GS-99-910
A phase 3 open-label multicenter study
of the safety of tenofovir disoproxil
with other antiretroviral agents for the
treatment of HIV-1 infected patients.
Viread
Module 5.3.5.2
Submitted in
response to
Specific Obligation
from the revised
Letter of
Undertaking
(EMEA/H/C/ 419)
August 2003
Specific
Obligation
Volumes
1–3
ACTG A5127
ACTG 5127 Executive Summary: A
Randomised, Phase II Controlled Trial
Comparing the Efficacy of Adefovir
Dipivoxil and Tenofovir Disoproxil
Fumarate for the Treatment of Hepatitis
B Virus in Subjects who are Coinfected with HIV (Based on
preliminary data for CROI 2005).
Viread
Available upon
request
Submitted in
response to a
Follow-Up
Measure
(EMEA/H/C/419)
May 2005
Follow-up
Measure
Volume 1
CONFIDENTIAL
Page 248
Volume
18AUG2010
Final
Clinical Study
Number
Study Title
Product
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Volume
GS-US-164-0107
(COMET)
Combination of Efavirenz and
Truvada (The COMET Study): A
Phase 4 Evaluation of Switching from
Twice Daily Zidovudine and
Lamivudine (Combivir) to a
Simplified, Once-Daily Regimen of
Co-formulated Emtricitabine and
Tenofovir Disoproxil Fumarate
(Truvada), in Virologically
Suppressed, HIV- Infected Patients
Taking Efavirenz
Truvada
Module 5.3.5.2
Submitted in
response to
Follow-Up
Measure
(EMEA/H/C/594)
September
2006
Follow-up
measure
Volumes
1-6
GS-DE-164-0106
A Phase 3, prospective,
nonrandomized, single-group,
open-label, 48-week, pilot study of
treatment switch from a regimen with
zidovudine and lamivudine plus a third
partner to a once-daily regimen
containing the fixed-dose combination
of tenofovir DF and emtricitabine in
combination with a third once-daily
partner in HIV infected subjects.
Truvada
Module 5.3.5.2
Submitted in
response to
Follow-Up
Measure
(EMEA/H/C/594)
June 2007
Follow-Up
Measure
Volume 1
GS-US-164-0115
A Phase 4, Prospective, Open-Label,
Multicenter Study of the Safety,
Efficacy, and Adherence in
HIV-Infected, Antiretroviral-Naïve
Subjects Treated with Simple
Once-Daily Regimen.
Truvada
Module 5.3.5.2
Submitted with
PSUR
(03 April 2008 to
02 April 2000)
June 2009
PSUR
Volume 1
CONFIDENTIAL
Page 249
18AUG2010
Final
Clinical Study
Number
C0840-00011
CONFIDENTIAL
Study Title
Product
Adefovir and tenofovir susceptibilities
of HIV-1 after 24-48 weeks of adefovir
dipivoxil therapy: genotypic and
phenotypic analyses of study
GS-96-408.
Truvada
Location within
FDC MAA
EU Procedure (&
number)
Date
Submitted
Dossier
Number/
Type
Available upon
request
Original MAA
(EMEA/H/C/594)
March 2004
Module 5
Page 250
Volume
Volume
150
18AUG2010
2.5 Clinical Overview
SECTION 2.5 – CLINICAL OVERVIEW- NOTE TO REVIEWER
The section 2.5 clinical overview document content submitted for Eviplera and
Edurant are the same apart from the following differences as outlined here:
5

Descriptions of changes proposed in the Eviplera product annexes are aligned
with the Eviplera proposed amendments. These descriptions differ slightly
from Edurant.

The following additions to the Eviplera clinical overview were made. These
changes were made to further explain the adverse event of decreased
lymphocytes that was seen in this study (based on the data in the clinical study
report). Additions are shown in underline and deletions in strikethrough from
Edurant overview:
Overview of Safety
5.1 TMC278IFD1003
No deaths, serious adverse events (SAEs), or Grade 4 adverse events (AEs) were
reported during this study. Grade 3 AEs were reported in 6 (30%) subjects during the
whole study. The most frequent Grade 3 AEs (reported in >1 subject in any treatment
phase) were lymphopenia (2 [18.2%] subjects during treatment with RPV 25 mg qd +
rifabutin 300 mg qd [Treatment C]] and none during Treatments A and B) and
myalgia (2 [10.0%] subjects during treatment with RPV 50 mg qd + rifabutin 300 mg
qd [Treatment B]).
The only grade 4 laboratory toxicity was grade 4 decreased absolute lymphocyte
count, which was reported in 4 (20.0%) subjects during Treatment B, and in 1 (9.1%)
subject during Treatment C compared to none during Treatment A. DecreasedTime to
onset of the Grade 4 events of decreased lymphocytes ranged from 11 to 14 days
following initiation of Treatment B or 18 days following initiation of Treatment C. In
4 subjects (3 on Treatment B, 1 on Treatment C), Grade 4 decreased lymphocyte
countcounts had normalized within 6 to 8 days (coinciding with 6 to 8 days after last
dose of study drug). In one further subject on Treatment B, lymphocyte counts had
improved to below normal 7 days after the Grade 4 event (while still on Treatment B)
and normalized at the next assessment (while no longer on study drug due to finishing
the treatment cycle). No concomitant treatment was administered to treat the
decreased lymphocyte counts in these subjects. Leukopenia is a knownvery common
(=> 10%) adverse effect for Rifabutin rifabutin, while lymphopenia and white blood
cell decreased are uncommon (=> 0.1% to < 1%) adverse effects for rifabutin
{24950}. The rifabutin SmPC recommends monitoring of white blood cell and
platelet counts periodically during treatment in Section 4.4, Special warnings and
precautions for use {24950}.
SECTION 2.5
CLINICAL OVERVIEW
SECTION 2.5 – CLINICAL OVERVIEW
EMTRICITABINE/RILPIVIRINE/TENOFOVIR DISOPROXIL
FUMARATE SINGLE-TABLET REGIMEN
Gilead Sciences International Ltd
26 JUNE 2013
CONFIDENTIAL AND PROPRIETARY INFORMATION
2.5 Clinical Overview Addendum
Final
TABLE OF CONTENTS
SECTION 2.5 – CLINICAL OVERVIEW ............................................................................................................1
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................2
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................3
INTRODUCTION..................................................................................................................................................4
1.
PRODUCT DEVELOPMENT RATIONALE...............................................................................................5
2.
OVERVIEW OF BIOPHARMACEUTICS...................................................................................................6
3.
OVERVIEW OF CLINICAL PHARMACOLOGY ......................................................................................7
3.1.
3.2.
3.3.
3.4.
Pharmacology/Virology ....................................................................................................................7
Clinical Pharmacodynamics..............................................................................................................7
Clinical Pharmacokinetics.................................................................................................................7
Potential for Drug Interactions..........................................................................................................7
3.4.1.
Rilpivirine .......................................................................................................................7
3.4.1.1.
Potential for RPV to Affect Other Drugs...................................................8
3.4.1.2.
Potential for Other Drugs to Affect RPV ...................................................8
4.
OVERVIEW OF EFFICACY......................................................................................................................11
5.
OVERVIEW OF SAFETY ..........................................................................................................................12
6.
BENEFITS AND RISKS CONCLUSIONS ................................................................................................14
7.
REFERENCES ............................................................................................................................................16
LIST OF IN-TEXT TABLES
Table 3-1.
CONFIDENTIAL
Interaction Trials or Predicted Interaction (Rilpivirine)................................................10
Page 2
26 June 2013
Final
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
adverse event
ARV
antiretroviral
CI
confidence interval
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CYP450
cytochrome P450 enzyme(s)
ECG
electrocardiogram
HIV(-1)
human immunodeficiency virus (-type 1)
MAH
Marketing Authorization Holder
QD
once daily
RPV
rilpivirine
RNA
ribonucleic acid
SAE
serious adverse event
TB
tuberculosis
CONFIDENTIAL
Page 3
26 June 2013
Final
INTRODUCTION
This document is an addendum to the initial Clinical Overview for Eviplera
(0000/Module 2.5 - Clinical Overview [18 August 2010]). It summarizes the data from a
completed Phase 1 clinical pharmacology study (TMC278IFD1003) in healthy subjects,
investigating the drug-drug interaction of rilpivirine (RPV) 25 mg once daily (qd) with
rifabutin.
Tuberculosis (TB) coinfection is highly prevalent in the population infected with the human
immunodeficiency virus (HIV) and disease management may require therapy for HIV
infection as well as TB. The rifamycins, rifampin and rifapentine, in combination with other
drugs, are part of preferred regimens for tuberculosis therapy {24933}. Drug-drug interactions
between rifamycins and antiretrovirals (ARVs) are, however, widespread, and it can be
difficult to design satisfactory concurrent regimens against TB and HIV {24951}. Rifabutin
(Mycobutin ®) is an antimycobacterial agent, structurally similar to rifampicin, with high in
vitro activity against many strains of Mycobacterium tuberculosis. {24950}. Rifabutin is a
less potent inducer of cytochrome P450 (CYP)3A enzyme activity than rifampin, and
therefore drug-drug interactions can be reduced as compared to those with rifampin.
Rifabutin is sometimes used in lieu of rifampin for treatment of TB, e.g., in cases where
drug-drug interactions preclude the use of rifampin {24931}.
A previously conducted study (TMC278-C125) with RPV 150 mg qd and rifabutin 300 mg
qd in healthy subjects, established the extent of the drug-drug interaction between RPV (a
CYP3A substrate) and rifabutin. Since the data from this study showed a substantial
reduction in RPV exposure, currently, coadministration of RPV (at the recommended dose of
25 mg qd) and rifabutin is contraindicated.
The current study (TMC278IFD1003) was conducted to further investigate the interaction
profile between rifabutin and RPV 25 mg qd and ways to overcome the interaction. It aimed
to evaluate different dosing regimens for RPV in combination with rifabutin in order to
provide guidance on dosing recommendations for the concurrent administration of RPV and
rifabutin in HIV-1 infected subjects.
The data described in this document support an update of the prescribing information for
Eviplera to provide guidance for the coadministration of Eviplera with rifabutin, i.e., when
Eviplera is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is
recommended to be taken concomitantly with Eviplera for the duration of rifabutin
coadministration.
Titles of all main sections of the Clinical Overview, with an indication of whether the section
required an update, are included in this addendum. Throughout the Clinical Overview,
“TMC278” was changed to “RPV”. This change has not been consistently indicated in this
addendum.
CONFIDENTIAL
Page 4
26 June 2013
1.
Final
PRODUCT DEVELOPMENT RATIONALE
No update is required for this section. Refer to the initial Clinical Overview for details
(0000/Module 2.5/Clinical Overview - Section 1 [18 August 2010]),
CONFIDENTIAL
Page 5
26 June 2013
2.
Final
OVERVIEW OF BIOPHARMACEUTICS
(0000/Module 2.5/Clinical Overview - Section 2 [18 Aug 2010]).
CONFIDENTIAL
Page 6
26 June 2013
3.
Final
OVERVIEW OF CLINICAL PHARMACOLOGY
Refer to the initial Clinical Overview for details (0000/Module 2.5/Clinical Overview Section 3 [18 August 2010]),
This section has been updated with the following additional information:
3.1.
Pharmacology/Virology
No update is required for this section.
3.2.
Clinical Pharmacodynamics
3.3.
Clinical Pharmacokinetics
3.4.
Potential for Drug Interactions
3.4.1.
Rilpivirine
TMC278IFD1003
Study Design
This was a Phase 1, open-label study in 20 healthy subjects, to explore the pharmacokinetics
of different dosing regimens of RPV in combination with rifabutin, at steady-state.
All subjects were scheduled to receive 3 different treatments (Treatments A, B, and C):

Treatment A: RPV 25 mg qd administered on Days 1 to 11;

Treatment B: RPV 50 mg qd administered on Days 1 to 11 + rifabutin 300 mg qd
administered on Days 1 to 17;

Treatment C: RPV 25 mg qd administered on Days 1 to 11 + rifabutin 300 mg qd
administered on Days 1 to 17 (this RPV regimen was determined based on an interim
pharmacokinetic analysis of Treatments A and B).
Further details on the design of this study are available in the Clinical Study Report
(Module 5.3.3.4/TMC278IFD1003-CSR - Section 3.1) and the addendum to the Summary of
Clinical Pharmacology Studies (Module 2.7.2/Summary of Clinical Pharmacology Studies
Addendum - Section 2.2.8).
CONFIDENTIAL
Page 7
26 June 2013
Final
Results
While the RPV 25 mg qd exposure was significantly reduced by rifabutin (a potent CYP3A
enzyme activity inducer) doubling the RPV dose (50 mg qd) was able to overcome this,
relative to RPV 25 mg qd alone.
For RPV 25 mg qd in the presence of rifabutin, the minimum plasma concentration (Cmin),
maximum plasma concentration (Cmax), and area under the plasma-concentration time curve
from time of intake until 24 hours after dosing (AUC24h) of RPV were 48%, 31%, and 42%
lower, respectively, compared to RPV alone at the same dose level. Similar results were
obtained in a previous study (TMC278-C125) with RPV at 150 mg qd.
For RPV 50 mg qd in the presence of rifabutin, Cmin was similar (90% confidence interval
[CI] within 80% to 125%) compared to RPV 25 mg qd alone, while Cmax and AUC24h were
43% and 16% higher, respectively, compared to RPV 25 mg qd alone, with the upper limit of
the 90% CI just above 125%. These increases in Cmax and AUC24h are not considered
clinically relevant.
Further details on the pharmacokinetic results of this study are available in the Clinical Study
Report (Module 5.3.3.4/TMC278IFD1003-CSR - Section 5) and the addendum to the
Summary of Clinical Pharmacology Studies (Module 2.7.2/Summary of Clinical
Pharmacology Studies Addendum - Section 2.2.8).
Conclusion
In conclusion, the pharmacokinetic data (Module 2.7.2/Summary of Clinical Pharmacology
Studies Addendum- Section 2.2.8) indicate that, throughout coadministration with rifabutin,
an additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly
with Eviplera for the duration of rifabutin coadministration.
3.4.1.1.
Potential for RPV to Affect Other Drugs
Rifabutin
The pharmacokinetics of rifabutin were not evaluated in the current study. However, it has
been previously shown (in study TMC278-C125) that the pharmacokinetics of rifabutin were
not affected by coadministration with RPV 150 mg qd (0000/Module 2.7.2/Summary of
Clinical Pharmacology Studies - Section 2.2.8.7 [19 Aug 2010]). No different results for
rifabutin pharmacokinetics are anticipated with lower RPV doses.
3.4.1.2.
Potential for Other Drugs to Affect RPV
This section has been updated with additions to the existing text indicated in bold and
deletions in strikethrough:
CONFIDENTIAL
Page 8
26 June 2013
Final
In general, the exposure to RPV can be affected by modulators of CYP3A enzyme activity
and by drugs that increase the gastric pH.
The primary metabolism of RPV is mainly catalyzed by CYP3A enzymes.
Therefore, coadministration of RPV and drugs that induce CYP3A could decrease RPV
plasma concentrations, which could potentially reduce the therapeutic effect of RPV.
This decrease in exposure was indeed shown in vivo by the results of drug-drug interaction
studies with rifampin and rifabutin, which both significantly decreased the exposure to RPV.
Based on this, RPV should not be used in combination with inducers of CYP3A
(e.g., rifampin, rifabutin, rifapentine, St John’s wort, systemic dexamethasone,
carbamazepine, oxcarbazepine, phenobarbital, phenytoin). For rifabutin, an alternative
dosing regimen has been established, i.e., when Eviplera is coadministered with
rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken
concomitantly with Eviplera for the duration of rifabutin coadministration.
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Table 3-1.
Final
Interaction Trials or Predicted Interaction (Rilpivirine)
Coadministration without Dose
Adjustment
Coadministration with specific
instructions
Coadministration Not
Recommended

N(t)RTIs, other than ddI
(e.g. TDF, ABC,
emtricitabine, 3TC,
stavudine, AZT)



boosted PIs LPV/rtv and
DRV/rtv1
ddI (which should be
administered on an empty
stomach) should be administered
separated in time from TMC278
RPV (which should be
administered with a meal).

raltegravir, maraviroc


ribavirin


azole antifungal agents
(including ketoconazole)
proton pump inhibitors
(e.g. omeprazole,
lansoprazole, rabeprazole,
pantoprazole, esomeprazole)

atorvastatin

estrogen-and/or
progesterone-based
contraceptives
when coadministering with
methadone, dose adjustment is
not needed when initiating
treatment with TMC278 RPV but
clinical monitoring for methadone
withdrawal symptoms is
recommended. Methadone
maintenance therapy may need to
be adjusted in some patients.
inducers of CYP3A
(e.g., rifampin, rifabutin,
rifapentine, St John’s wort,
systemic dexamethasone,
carbamazepine,
oxcarbazepine,
phenobarbital, phenytoin).

paracetamol
1

H2-antagonists (e.g. famotidine)
or antacids, can be
coadministered if separated in
time.

clarithromycin, erythromycin, and
troleandomycin may cause an
increase in the plasma
concentrations of RPV.
Where possible, alternatives such
as azithromycin should be
considered.

When Eviplera is
coadministered with rifabutin,
an additional 25 mg tablet of
rilpivirine per day is
recommended to be taken
concomitantly with Eviplera for
the duration of rifabutin
coadministration.
The combination of RPV with other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir,
tipranavir/ritonavir) or unboosted PIs (atazanavir, indinavir, nelfinavir) has not been studied; coadministration may cause
an increase in the plasma concentrations of RPV.
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4.
Final
OVERVIEW OF EFFICACY
(0000/Module 2.5/Clinical Overview - Section 4 [18 August 2010]),
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5.
Final
OVERVIEW OF SAFETY
5.1 TMC278IFD1003
For detailed information on the safety data described in this section, refer to the Clinical
Study Report (Module 5.3.3.4/TMC278IFD1003-CSR - Section 6).
No deaths, serious adverse events (SAEs), or Grade 4 adverse events (AEs) were reported
during this study. Grade 3 AEs were reported in 6 (30%) subjects during the whole study.
The most frequent Grade 3 AEs (reported in >1 subject in any treatment phase) were
lymphopenia (2 [18.2%] subjects during treatment with RPV 25 mg qd + rifabutin 300 mg qd
[Treatment C] and none during Treatments A and B) and myalgia (2 [10.0%] subjects during
treatment with RPV 50 mg qd + rifabutin 300 mg qd [Treatment B]).
Eight (40.0%) subjects stopped RPV as well as rifabutin intake and discontinued the study
due to AEs. The most frequent AEs leading to discontinuation (reported in >1 subject in any
treatment phase) were headache, myalgia, pyrexia, and arthralgia. None of these AEs
occurred during treatment with RPV 25 mg qd alone (Treatment A). Headache was reported
in 3 (15.0%) and 1 (9.1%) subjects during Treatment B and Treatment C, respectively,
myalgia in 3 (15.0%) and 1 (9.1%) subjects, respectively, and pyrexia in 2 (10.0%) and 1
(9.1%) subjects, respectively.
The most frequently reported AEs (reported in >3 subjects in any treatment phase) were
headache, myalgia, pyrexia, diarrhea, influenza-like illness, pruritus, and dizziness. None of
these AEs occurred in Treatment A, except for headache in 1 (5.6%) subject. Headache was
reported in 9 (45.0%) and 2 (18.2%) subjects during Treatment B and Treatment C,
respectively, myalgia in 6 (30.0%) and 5 (45.5%) subjects, respectively, and pyrexia in 5
(25.0%) and 1 (9.1%) subjects, respectively. Diarrhea was reported in in 4 (20.0%) and 3
(27.3%) subjects, respectively, influenza-like illness in 5 (25.0%) and 1 (9.1%) subjects,
pruritus in 4 (20.0%) and 1 (9.1%) subjects, and dizziness in 4 (20.0%) and 1 (9.1%)
subjects, respectively.
Most of these AEs reported during the coadministration phase are AEs known to have been
reported with RPV in other Phase 1 studies (headache, dizziness, pruritus) and/or rifabutin
(headache, myalgia, pyrexia, diarrhea, flu-like syndrome). Most of these AEs were also
reported during the coadministration phase of a previous study (TMC278-C125) with
rifabutin and 150 mg qd RPV, with similar or lower frequencies.
The only grade 4 laboratory toxicity was grade 4 decreased absolute lymphocyte count,
which was reported in 4 (20.0%) subjects during Treatment B, and in 1 (9.1%) subject during
Treatment C compared to none during Treatment A. Time to onset of the Grade 4 events of
decreased lymphocytes ranged from 11 to 14 days following initiation of Treatment B or 18
days following initiation of Treatment C. In 4 subjects (3 on Treatment B, 1 on Treatment C),
Grade 4 decreased lymphocyte counts had normalized within 6 to 8 days (coinciding with 6
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Final
to 8 days after last dose of study drug). In one further subject on Treatment B, lymphocyte
counts had improved to below normal 7 days after the Grade 4 event (while still on
Treatment B) and normalized at the next assessment (while no longer on study drug due to
finishing the treatment cycle). No concomitant treatment was administered to treat the
decreased lymphocyte counts in these subjects. Leukopenia is a very common (=> 10%)
adverse effect for rifabutin, while lymphopenia and white blood cell decreased are
uncommon (=> 0.1% to < 1%) adverse effects for rifabutin {24950}. The rifabutin SmPC
recommends monitoring of white blood cell and platelet counts periodically during treatment
in Section 4.4, Special warnings and precautions for use {24950}.
Abnormalities in ECG parameters were scarce and no AEs related to vital signs parameters
were reported.
The safety and tolerability of RPV 25 mg qd administered alone for 11 days was better than
that of RPV 25 or 50 mg qd administered for 11 days together with rifabutin 300 mg qd for
17 days. There was a higher frequency and grading of AEs and laboratory abnormalities as
well as a higher number of dropouts when RPV was coadministered with rifabutin, as
compared to RPV alone. However, no new safety issues were identified for RPV alone or in
combination with rifabutin, taking into account the known safety and tolerability profiles of
both RPV and rifabutin.
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6.
Final
BENEFITS AND RISKS CONCLUSIONS
No new safety issues were identified for RPV alone or in combination with rifabutin, taking
into account the known safety and tolerability profiles of both RPV and rifabutin.
The pharmacokinetic findings of this drug-drug interaction study with RPV and rifabutin
indicate that when Eviplera is coadministered with rifabutin, an additional 25 mg tablet of
rilpivirine per day is recommended to be taken concomitantly with Eviplera for the duration
of rifabutin coadministration. The product information is proposed to be updated with the
new pharmacokinetic data of this drug-drug interaction study in order to provide appropriate
guidance to prescribers regarding the coadministration of Eviplera and rifabutin.
The Marketing Authorization Holder (MAH), therefore, proposes to update the Summary of
Product Characteristics for Eviplera as follows:

The Posology section is updated to reflect the appropriate dose for Eviplera when
coadministered with rifabutin i.e., when Eviplera is coadministered with Rifabutin, an
additional 25 mg tablet of rilpivirine per day is recommended to be taken concomitantly
with Eviplera for the duration of rifabutin coadministration.

Rifabutin is removed from the Contraindications section.

The concomitant use not recommended section is revised to allow Eviplera to be
administered concomitantly with RPV in the case of dose adjustment due to rifabutin.

Table Interactions and dose recommendations with other medicinal products is updated
with pharmacokinetic data for RPV and rifabutin obtained in the drug-drug interaction
study TMC278IFD1003.
In the Package leaflet, the following changes are proposed:

Rifabutin is deleted from the list of medicines that should not be taken in combination
with Eviplera.

Rifabutin is added to the list of medicines that may influence the effects of Eviplera or
other medicines, when taken together with Eviplera.

Information that your doctor may need to give you an additional dose of rilpivirine to
treat your HIV infection is added.
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Final
Guidance for Clinical Use of FTC/RPV/TDF Drug Interactions
A previous study (TMC278-C125) with RPV 150 mg qd (a CYP3A substrate) and rifabutin
(a CYP3A inducer) showed a substantial reduction in RPV exposure when combined. Based
on these earlier results, the coadministration of Eviplera (containing 25 mg RPV) qd and
rifabutin was contraindicated.
The current study (TMC278IFD1003) was conducted to further establish the interaction
profile between rifabutin and RPV 25 mg qd and ways to overcome the interaction. While the
RPV 25 mg qd exposure was significantly reduced by rifabutin, doubling the RPV dose (50
mg qd) was able to overcome this relative to RPV 25 mg qd alone. Therefore when Eviplera
is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine per day is
recommended to be taken concomitantly with Eviplera for the duration of rifabutin
coadministration.
Exposure Response Relationship
This section has been updated with additions to the existing text indicated in bold and
deletions in strikethrough:
Coadministration of RPV with CYP3A inducers may cause significant decreases in RPV
plasma concentrations, as was shown in drug-drug interaction studies with rifampin and
rifabutin, which decreased the mean exposure to RPV by 80% and 42%, respectively.
Therefore, RPV should not be coadministered with CYP3A inducers (e.g. rifampin, rifabutin,
rifapentin, phenytoin, carbamazepine, oxcarbamazepine, phenobarbital, systemic
dexamethasone and products containing St John’s wort). For rifabutin, an alternative
dosing regimen has been established, i.e., when Eviplera is coadministered with
rifabutin, an additional 25 mg tablet of rilpivirine per day is recommended to be taken
concomitantly with Eviplera for the duration of rifabutin coadministration.
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7.
Final
REFERENCES
24931
Centers for Disease Control and Prevention. Targeted tuberculin testing and
treatment of latent tuberculosis infection. American Thoracic Society. MMWR
Recomm Rep 2000;49 (RR-6):1-51.
24933
Norton BL, Holland DP. Current management options for latent tuberculosis: a
review. Infection and drug resistance 2012;5:163-73.
24950
Mycobutin (Rifabutin) Capsule (150 mg) for oral administration. Summary of
Product Characteristics (United Kingdom). Pfizer, March 2012.
24951
Walubo A. The role of cytochrome P450 in antiretroviral drug interactions. Expert
Opin Drug Metab Toxicol 2007;3 (4):583-98.
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