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Title: BMS Data Update


1
BMS Data Update
  • Dr Keith Aizen and Victoria Adamson
  • Bristol-Myers Squibb

Prescribing and adverse event reporting
information can be found at the end of this
presentation
Date of preparation July 2009 Job Bag No
HIV/0709/2983 MC/HIV/ATR/0709/0008
2
BMS Virology Portfolio
3
DDI and D4T safety update
4
Topics
  • Peripheral neuropathy
  • CV risk
  • Hepatotoxicity

5
Peripheral neuropathy
6
Study 903 Patients lt 50 Copies/mL
Intent to Treat (MissingFailure)
73 69
Patients with HIV-1 RNA lt 50 c/mL
Weeks
Adapted from Gallant et al JAMA July 14 2004 vol
202 191-201
7
Study 903 Selected Toxicities Associated with
Mitochondrial Dysfunction through Week 144
d4T3TCEFV (n301)
TDF3TCEFV (n299)
(All Grades) Week 48
Week 144 Week 48 Week 144 Patients () with
Events 9 (3) 17 (6) 30 (10) 82 (27)
Peripheral Neuritis/ Neuropathy 6 (2) 9
(3) 20 ( 7) 31 (10) Lipodystrophy 3
(1) 9 (3) 11 ( 4) 57 (19) Lactic
Acidosis 0 0 3 ( 1) 3 ( 1)
Pancreatitis 0 0 0 0
Investigator Defined p value lt
0.001 p 0.013
Adapted from Gallant et al JAMA July 14 2004 vol
202 191-201
8
Do treatments for HIV drug induced peripheral
neuropathy work ?
  • Pregabalin1
  • Improved pain but no better than placebo
  • Acetyl L Carnitine2
  • After 14 days no difference to placebo by ITT,
    but
  • significant difference by EE analysis

Simpson D IAC Aug 2008 abstract THAB0301 Youle et
al HIV Medicine (2007),8, 241-250
9
Morphological changes
10
What do BHIVA Guidelines recommend ?
  • Lipoatrophy
  • Replace D4T or AZT
  • Surgical intervention
  • Lipohypertrophy
  • Metformin if insulin resistance is present
  • GH long term data required

Gazzard et al, HIV Medicine (2008) vol 9 563-608
11
CV risk
12
NRTIs and Risk of MI Recent Exposure to Each
Drug
RR yes/no 95 CI

ZDV
ddI
ddC
d4T
3TC
ABC
TDF
138,109
74,407
29,676
95,320
152,009
53,300
39,157
PYFU
523
331
148
405
554
221
139
MI
recent use current or within the last 6
months not shown (low number of patients
currently on ddC)
Lundgren JD, et al CROI Oral Abstract 44LB
13
  • Newly described
  • Unknown cause in HIV infected Patients
  • Postulated to be associated with DDI

Kovari et al Clinical infectious diseases 200949
626-635
14
Literature review of noncirrhotic portal
hypertension
Kovari et al Clinical infectious diseases 200949
626-635
15
Study design
  • Nested case control study
  • 15 patients with NCPH and 75 controls in the
    Swiss HIV cohort study
  • Matched by HIV duration, no viral hepatitis and
    follow up to at least the date of NCPH diagnosis

Kovari et al Clinical infectious diseases 200949
626-635
16
Definition of NCPH in this study
  • Endoscopically confirmed varices
  • Presenting symptoms include increased liver
    enzymes, heamatamesis or ascites

Kovari et al Clinical infectious diseases 200949
626-635
17
Kovari et al Clinical infectious diseases 200949
626-635
18
Bivariable odds ratios for the effect of DDI on
NCPH and ORs for the covariables before and after
adjustment for DDI
Kovari et al Clinical infectious diseases 200949
626-635
19
Study Conclusions
  • Strong association between prolonged DDI exposure
    and development of NCPH
  • An important finding of this study is that
    long-term toxicity of antiretroviral drugs might
    emerge only after decades. As persons with HIV
    infection in industrialized countries live longer
    and ART exposure is prolonged, we need to be
    alert for novel clinical manifestations
    attributable to drug-related adverse events

Kovari et al Clinical infectious diseases 200949
626-635
20
Naïve patients BHIVA 2008 What to start with?
It is the Writing Groups view that EFV should
be considered first line in all patients. This is
Based upon its efficacy, durability, toxicity
profile, convenience and cost
A
B
NRTI TDF ABC
C
NRTI FTC 3TC

  • NNRTI
  • EFVa

preferred
NNRTI NVP PI ATV/r fAPV/r LPV/r SQV/r
  • NRTI
  • AZTgt
  • ddI

alternative
aexcept in women who may wish to become pregnant
Only when CD4 lt250 cells/mm3
in females, lt400 cells/mm3 in males Where
established cardiovascular disease risk factors
and a PI required gt Co-formulated
as Combivir Co-formulated as
Kivexa Co-formulated
as Truvada
Gazzard et al, HIV Medicine (2008) vol 9 563-608
21
ACTG 5142 Study Co-Primary Endpoint Time to
Virologic Failure (VF)
EFV 2 NRTIs arm had a statistically
significantly longer time to virologic failure
than the LPV/r 2 NRTIs arm
0
24
48
72
96
120
144
Number of Patients
Weeks After Randomization
EFV 2 NRTIs LPV/r 2 NRTIs EFV LPV/r 250 253 250 210 210 215 186 185 189 173 168 181 142 140 149 73 74 73 19 14 17
Adapted from Riddler SA, et al. N Engl J Med.
20083582095-2106.
22
903E Study The Safety and Efficacy of Tenofovir
DF (TDF) in Combination with Lamivudine (3TC) and
Efavirenz (EFV) in Antiretroviral-naïve Patients
Through 7 Years
  • Methods
  • Patients in selected sites (Argentina, Brazil,
    and Dominican Republic) rolled over into a 7-year
    (336-week) open-label extension phase (903E)
  • Data obtained from patients originally randomized
    to TDF and participating in 903E were analyzed
  • Study Design

TDF OD
EFV OD
3TC BID
d4t placebo BID
n 86
Study 903E
TDF QD
EFV QD
3TC QD
(OPEN-LABEL) (OPEN-LABEL)
3 Years (144 Weeks)
7 Years (336 Weeks)
Study 903
d4t BID
EFV QD
3TC BID
TDF placebo QD
Adapted from Madruga JVR, et al , ICDT 2008,
Poster P4
23
903E Study HIV-1 RNA, CD4, and Resistance
Proportion with HIV-1 RNA lt400
copies/mL through 7 Years (MF)
Proportion with HIV-1 RNA lt50
copies/mL through 7 Years (MF)
100
80
80
n86
60
with HIV RNA lt50 copies/mL
40
20
0
0
1
2
3
4
5
6
7
Years
Mean Change from Baseline in CD4 through 7 Years
  • Resistance
  • 4 patients discontinued due to virologic failure
  • 2 Wild type genotypes
  • 1 T69N, M184V, K103N at Week 240
  • 1 M184M/V, K103 K/N, V108V/I, P225P/H,
    T69A/T,K219K/R, K70K/E/G/R at Week 336
  • No K65R

500
459
450
400
350
300
Mean Change in cells/mm3
250
200
150
100
50
0
0
1
2
3
4
5
6
7
Years
n 86 85 85 84 82 77 73 71
Adapted from Madruga JVR, et al , ICDT 2008,
Poster P4
24
903E Study Median Total Limb Fat (IQR) Years 2-7
12
10
8.0a
8
6.7
Plt0.001a
Median Limb Fat in kg
6
4
2
0
0
1
2
3
4
6
5
7
Year
TDF 3TC EFV n 69 69 65 61 59 58
  • aP-value for change from Year 2 using Wilcoxon
    Signed Rank test

Adapted from Madruga JVR, et al , ICDT 2008,
Poster P4
25
903E Study Investigators Conclusions
  • Through 7 years of therapy in antiretroviral-naïv
    e patients, TDF 3TC EFV demonstrated the
    following
  • Sustained, durable antiretroviral efficacy
  • Continued CD4 cell count increases
  • No discontinuations due to renal adverse events
  • No evidence of clinically relevant bone effects
  • Significant increases in limb fat from Years 2
    through 7

Madruga JVR, et al , ICDT 2008, Poster P4
26
  • Efficacy of boosted Reyataz Atazanavir
    (ATV/r) in naïve patients

27
CASTLE study design
Screening/enrolment
HIV RNA ?5000 c/mL, no CD4 cell count
restriction Randomization (n883) Stratified HIV
RNA lt100 000 c/mL vs ?100 000 c/mL geographic
region
(11)
ATV/r 300/100 mg QD (n440)
LPV/r 400/100 mg BID (n443)
TDF/FTC 300/200 mg QD
TDF/FTC 300/200 mg QD
Primary endpoint Proportion of subjects with HIV
RNA lt50 c/mL at Week 48 Principal analysis
ITT-confirmed virological response (CVR) (NCF)
ATV/r, atazanavir/ritonavir BID, twice daily
FTC, emtricitabine LPV/r, lopinavir/ritonavir
QD, once daily TDF, tenofovir Adapted from
Molina J-M, et al. Poster presented at the joint
ICAAC / IDSA, Washington, USA, 25-28 October
2008. Poster H-1250d
28
Primary efficacy endpoint ITT-confirmed
virological response (NCF)
ATV/r (n440) LPV/r (n443)
100
80
60
Responders, (SE)
40
HIV RNA lt50 c/mL 78 ATV/r vs 76
LPV/r Difference estimate 1.7 (95 CI, -3.8,
7.1)
20
0
BL
12
24
36
48
4
Time (weeks)
ATV/r has noninferior antiviral efficacy compared
with LPV/r
Supporting analyses ITTTLOVR HIV RNA lt50 c/mL
ATV/r 78, LPV/r 76 1.9 (-3.6, 7.4) OTVROC
HIV RNA lt50 c/mL ATV/r 84, LPV/r 87 -3.5
(-8.7, 1.8)
Adapted from Molina J-M, et al. Lancet
2008372646-655
29
Week 96 Results HIV RNA lt50 c/mL (CVR NCF)
ATV/r (n440) LPV/r (n443)
100
80
60
plt0.05
Responders ()
40
HIV RNA lt 50 c/mL 74 ATV/r vs 68
LPV/r Difference estimate 6.1 (95 CI,
0.312.0)
20
0
BL
12
24
36
48
4
60
72
84
96
Time (weeks)
ATV/r has noninferior antiviral efficacy compared
with LPV/r
Supporting analyses ITTTLOVR HIV RNA lt50 c/mL
ATV/r 70, LPV/r 63 6.6 (0.4, 12.7) OTVROC
HIV RNA lt50 c/mL ATV/r 89, LPV/r 88 1.6
(-3.1, 6.2)
Adapted from Molina J-M, et al. Poster presented
at the joint ICAAC / IDSA, Washington, USA, 25-28
October 2008. Poster H-1250d
30
As randomised Week 96 CD4 mean change from
baseline
300
250
ATV/r (n440) LPV/r (n443)
200
CD4 mean change (cells/mm3)
150
100
Increase in mean CD4 cells/mm3 268 ATV/r vs 290
LPV/r Estimated difference -21.2 (95 CI -43.3,
0.9)
50
0
BL
12
24
36
48
4
60
72
84
96
Time (weeks)
Adapted from Molina J-M, et al. Poster presented
at the joint ICAAC / IDSA, Washington, USA, 25-28
October 2008. Poster H-1250d
31
Adverse events Summary
ATV/r (n441) n () LPV/r (n437) n ()
Serious adverse events Serious adverse events Serious adverse events 63 (14) 50 (11)
Grade 24 treatment-related AEsa Grade 24 treatment-related AEsa Grade 24 treatment-related AEsa 133 (30) 140 (32)
Grade 24 treatment-related AEs ?3a,b Jaundice Jaundice 18 (4) 0
Grade 24 treatment-related AEs ?3a,b Nausea Nausea 18 (4) 33 (8)
Grade 24 treatment-related AEs ?3a,b Diarrhoea Diarrhoea 11 (2) 54 (12)
  • 3 discontinuations on ATV/r due to
    jaundice/hyperbilirubinaemia
  • None between Weeks 48 96
  • 7 subjects discontinued due to diarrhoea (all on
    LPV/r)
  • 2 between Weeks 48 and 96
  • 39 (9) of subjects on ATV/r versus 96 (22) on
    LPV/r initiated antidiarrhoeal medications
  • Renal all grade AEs 4 in both arms
  • 1 discontinuation due to renal AE in each arm

aThrough 96 weeks bExcluding laboratory
abnormalities reported as AEs Molina J-M, et al.
Poster presented at the joint ICAAC/IDSA,
Washington, USA, 25-28 October 2008. Poster
H-1250d
32
Grade 2-4 diarrhoea through 96 weeks
Patients ()
Molina J-M, et al. Poster presented at the joint
ICAAC/IDSA, Washington, USA, 25-28 October 2008.
Poster H-1250d
33
Fasting lipids NCEP and ratios
ATV/r (n441) ATV/r (n441) LPV/r (n437) LPV/r (n437)
NCEP shifts up (1 category)
Total cholesterol 16 16 29 29
LDL cholesterol 32 32 40 40
Triglycerides 23 23 49 49
Baseline Week 96 Baseline Week 96
Total HDL cholesterol ratio gt5 23 17 27 27
2 of subjects on ATV/r versus 9 of subjects on
LPV/r initiated lipid-lowering drugs on study
Molina J-M, et al. Poster presented at the joint
ICAAC/IDSA, Washington, USA, 25-28 October 2008.
Poster H-1250d
34
Findings from CASTLE sub-analyses
Boosted Reyataz was efficacious generally
well-tolerated irrespective of race
Mc Grath et al, IAC 2008 August 2008, Poster
TUPE0058
Boosted Reyataz was efficacious generally
well-tolerated irrespective of gender
Absalon J, et al. XVII IAC, Mexico City, 3-8
August 2008, Poster TUPE0062
Boosted Reyataz was efficacious generally
well-tolerated irrespective of HBV/HCV status
Perez-Elias MJ, et al. IAS 2005 Poster
TuPe1.1C25 Absalon J, et al. ICDT, Glasgow, UK,
9-13 November 2008, Poster 136
Boosted Reyataz resulted in improvements in
patients quality of life
Su et al, IAC 2008 August 2008, POSTER
TUPE0060
Boosted Reyataz was an effective and
well-tolerated in advanced HIV-infected
treatment-naïve patients

Adapted from Molina JM, et al. 48th ICAAC,
Washington, DC, USA, 25-26 October 2008. Poster
H-1250d
35
Boosted Reyataz was efficacious generally
well-tolerated irrespective of race
Mc Grath et al, IAC 2008
36
Boosted Reyataz was efficacious generally
well-tolerated irrespective of gender
  • Efficacy
  • ATV/r QD demonstrated noninferior antiviral
    efficacy to LPV/r BID (both TDF/FTC) in
    ARV-naïve patients
  • Virological response rates were consistently high
    in men and women
  • Both regimens were associated with robust
    increases in CD4 cell count regardless of gender

Gender HIV RNA lt50 copies/mL (CVR NCF) at Week 48 Responder/evaluable () HIV RNA lt50 copies/mL (CVR NCF) at Week 48 Responder/evaluable () Mean CD4 cell count change from baseline (SE), cells/mm3 Mean CD4 cell count change from baseline (SE), cells/mm3 Mean absolute CD4 cell count at Week 48 (SE), cells/mm3 Mean absolute CD4 cell count at Week 48 (SE), cells/mm3
ATV/r LPV/r ATV/r LPV/r ATV/r LPV/r
Female 105/138 (76) 101/139 (73) 199 (11.8) 221 (12.5) 406 (16.5) 417 (15.4)
Male 238/302 (79) 237/304 (78) 205 (8.7) 219 (8.9) 418 (12.2) 448 (12.0)
Absalon J, et al. XVII IAC, Mexico City, 3-8
August 2008, Poster TUPE0062
37
Boosted Reyataz was efficacious generally
well-tolerated irrespective of HBV/HCV status
CASTLE ATV/r Liver Function and Bilirubin
Bilirubin and ALT levels
Coinfected
Not coinfected
2.4
ALT gt200 UI/mL or ALT gt3.5 x baseline abnormal
levels
Median total bilirubin
5
1.9 md/dL
2.0
1.8 mg/dL
4
1.6
pNS
Subjects with moderate-to-severe ALT elevation
()
3
1.2
Total bilirubin (mg/dL)
1.90
2
0.6 mg/dL
0.8
1.10
0.4 mg/dL
1
0.4
0
0
n176
n116
n107
n75
n176
n107
n116
n75
0
0
Baseline
Month 6
Baseline
Month 6
nsubjects with measurements
Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25
38
CASTLE Efficacy by Hepatitis B/C coinfection
  • Virological and immunological responses at Week
    48 were similar in hepatitis uninfected and
    coinfected patients in the ATV/r and LPV/r arms
  • Responses were comparable in coinfected patients
    treated with ATV/r or LPV/r

HIV RNA lt50 copies/mL (CVR NCF) at Week 48 n/N () HIV RNA lt50 copies/mL (CVR NCF) at Week 48 n/N () Mean CD4 cell count change from baseline (SE), cells/mm3 Mean CD4 cell count change from baseline (SE), cells/mm3

ATV/r LPV/r ATV/r LPV/r
HBV/HCV- 300/378 (79) 301/391 (77) 204 (7.2) 291 (7.7)
HBV/HCV 42/61 (69) 37/51 (73) 196 (26.1) 228 (21.7)
Absalon J, et al. ICDT, Glasgow, UK, 9-13
November 2008, Poster 136
39
CASTLE Adverse Events by Hepatitis B/C
Coinfection
  • Grade 24 treatment-related AEs through Week 48
    As-treated patients, n ()

ATV/r ATV/r LPV/r LPV/r
HBV/HCV- (n380) HBV/HCV (n60) HBV/HCV- (n385) HBV/HCV (n51)
Any AE 99 (26) 16 (27) 110 (29) 19 (37)
GI disorders 36 (9) 3 (5) 71 (18) 11 (22)
Hyperbilirubinaemia 23 (6) 10 (17) 1 (lt1) 0
Jaundice 16 (4) 2 (3) 0 0
  • Hepatitis uninfected and coinfected patients
    treated with ATV/r had a more favourable lipid
    profile compared with LPV/r-treated patients
  • Lipid profiles were similar in hepatitis
    uninfected and coinfected patients in both the
    ATV/r and LPV/r treatment arms

Absalon J, et al. ICDT, Glasgow, UK, 9-13
November 2008, Poster 136
40
Summary Role of ATV in Coinfected Patients
  • ATV hyperbilirubinaemia is common in clinical
    practice, particularly when ATV is used with RTV
    (boosting) and among patients with altered
    bilirubin levels at baseline1
  • Pre-existing Gilberts syndrome predisposes
    patients to higher bilirubin levels with ATV2
  • Severe hyperbilirubinaemia occurs in only a
    minority of patients1
  • Neither HBV nor HCV co-infection seemed to
    increase the risk of hyperbilirubinaemia and
    hyperbilirubinaemia did not seem to increase risk
    of flares in liver transaminases1
  • Results confirm that hyperbilirubinaemia is
    manageable in clinical practice and an innocent
    phenomenon in most cases as far as liver
    tolerability is concerned1
  • Patients with hepatic impairment ATV/r should be
    used with caution in patients with mild hepatic
    impairment. ATV should not be used in patients
    with moderate to severe hepatic impairment3

1. Lapadula G, et al. EACS 2007, Poster 9.6/03
2. Lankisch TO, et al. Hepatology
20064413241332, 3. http//www.emea.europa.eu/hu
mandocs/Humans/EPAR/reyataz/reyataz.htm
41
Boosted Reyataz was an effective and
well-tolerated in advanced HIV-infected
treatment-naïve patients
Egger M, 14th CROI, 2007, Abstract 62. ART Cohort
Collaboration http//www.art-cohort-collaboration.
org
42
CASTLE 96-Week Efficacy According to Baseline
Viral Load
ITT-confirmed virological response (NCF) at Week
96 by qualifying HIV viral load
100
90
Responders () lt50 c/mL
75
74
80
70
66
70
60
ATV/r
50
LPV/r
40
30
20
10
n218
n223
n225
n217
0
HIV RNA lt100 000 copies/mL
HIV RNA 100 000 copies/mL
Adapted from Molina JM, et al. 48th ICAAC,
Washington, DC, USA, 25-26 October 2008, Poster
H-1250d
43
CASTLE 96-Week Efficacy by Baseline CD4 Cell
Count
pns
pns
100
90
78
76
80
Responders () lt50 c/mL
71
71
70
69
69
70
58
60
50
40
30
20
10
0
Adapted from Molina JM, et al. 48th ICAAC,
Washington, DC, USA, 25-26 October 2008. Poster
H-1250d
44
Treatment Experienced patients
  • Evolving goal of antiretroviral therapy for all
    HIV-positive patients regardless of the extent of
    previous treatment experience
  • Achieve and maintain an undetectable VL1,2
  • Achievable for majority of patients with
    currently available agents
  • Patients with therapy options
  • Consider changing regimen sooner rather than
    later
  • Change 2 drugs in the regimen to active agents
  • The use of an agent from a new drug class is
    likely to be effective

1. Hammer SM, et al. JAMA. 2006296827-843. 2.
BHIVA website http//www.bhiva.org/files/file1030
835.pdf (Pre-press version of 2008 BHIVA
Guidelines for HIV Anti-Retroviral Treatment on
page 11-Accessed on 04 September 2008)
45
Evolution of Once-daily ATRIPLA Dosing
Efavirenz (Sustiva)
ATRIPLA
Emtricitabine (Emtriva)
Truvada
Tenofovir DF (Viread)
Sustiva SmPC, September 2008 Viread SmPC,
September 2008 Emtriva SmPC, September
2008 Truvada SmPC, December 2008 ATRIPLA SmPC,
December 2008
The pills shown are not the actual size
46
The ATRIPLA Indication in Europe
  • ATRIPLA is a fixed-dose combination of
    efavirenz, emtricitabine and tenofovir disoproxil
    fumarate
  • It is indicated for the treatment of HIV-1
    infection in adults with virological suppression
    to HIV-1 RNA levels of lt50 copies/mL on their
    current combination antiretroviral therapy for gt3
    months
  • Patients must not have experienced virological
    failure on any prior ART and must be known not to
    have harboured virus strains with mutations
    conferring significant resistance to any of the
    three components contained in ATRIPLA before
    initiation of their first ART regimen
  • The demonstration of the benefit of ATRIPLA is
    primarily based on 48-week data from a clinical
    study in which patients with stable virological
    suppression on a combination ART changed to
    ATRIPLA
  • No data are currently available from clinical
    studies with ATRIPLA in treatment-naïve or
    heavily pretreated patients

ATRIPLA SmPC
47
Efficacy of ATRIPLA Study AI266073 Design
Phase IV, multicentre (55 US sites), open-label
study (N 300)
  • Stable ARV Regimen
  • (PI or NNRTI 2 NRTIs) for 3 months
  • VL lt200 copies/mL
  • No History of Virologic Failure

EFV/FTC/TDF Once Daily
Switch
Randomisation 21
Stratify by PI or NNRTI
Continue
Stayed on Baseline Regimen
Week
0
24
48
Primary Endpoint assess non-inferiority of
EFV/FTC/TDF vs. SBR in terms of maintenance of
HIV-1 RNA lt200 copies/mL through Week 48 by
TLOVRanalyses
Time to loss of Virologic Response Algorithm
SBR stayed on baseline regimen
Adapted from Young B, et al., Glasgow 2008
Poster P061
ATRIPLA is not indicated for treatment-naïve
patients in the EU
48
ARV Baseline Regimen
PIs (53)
NNRTIs (47)
FPV (3)
IDV (2)
ATV (2)
NVP 11
ATV/r 15
NFV (7)
SQV/r (2)
LPV/r 13
FPV/r (9)
EFV 36
a. Most frequent NNRTI regimens were EFVAZT/3TC
(16), EFVABC/3TC (6), EFVTDF3TC (5) b.
Most frequent PI regimens were ATV/r FTC/TDF
(13), LPV/r FTC/TDF (6), FPV/rABC/3TC (4)
Adapted from DeJesus EACS 2007, Madrid, Spain
ATRIPLA is not indicated for treatment-naïve
patients in the EU
49
Primary Endpoint Analysis Percentage of
Patients with HIV-1 RNA lt200 copies/mL Through 48
Weeks (TLOVR)
Treatment Difference (EFV/FTC/TDF SBR) and 95
CI 1.1 (6.7, 8.8)
89
88
Percent with Virologic Response
  • The primary endpoint of non-inferiority of
    EFV/FTC/TDF to SBR was demonstrated

Adapted from Young B, et al., Glasgow 2008
Poster P061
ATRIPLA is not indicated for treatment-naïve
patients in the EU
50
Efficacy Analysis by Prior Treatment Stratum
Week 48
Stratum at Baseline Stratum at Baseline Stratum at Baseline Stratum at Baseline
Patients Below HIV-1 RNA Threshold () Prior NNRTI Prior NNRTI Prior PI Prior PI
Patients Below HIV-1 RNA Threshold () EFV/FTC/TDF (N  95) SBR (N  45) EFV/FTC/TDF (N  108) SBR (N  52)
lt200 copies/mL lt200 copies/mL lt200 copies/mL lt200 copies/mL lt200 copies/mL
TLOVRa 92 84 87 90
MEb 100 100 100 100
lt50 copies/mL lt50 copies/mL lt50 copies/mL lt50 copies/mL lt50 copies/mL
TLOVR 92 82 83 87
ME 100 97 98 98
a. Time to loss of virologic response algorithm
(NCF) b. Missing data (for any reason) was
excluded in this analysis PNS for all
comparisons in both strata
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Young B, et al., Glasgow 2008
Poster P061
51
Discontinuations Due to Adverse Events
N () EFV/FTC/TDF (N203) SBR (N97)
Any Adverse Event 10 (5) 1 (1)
Nervous system symptoms (NSS)a 5 (2) 0
Increased creatinineb 2 (lt1) 0
Acute hepatitis 1 (lt1) 0
AST/ALT elevation 1 (lt1) 0
Acute pancreatitis 1 (lt1) 0
Gastritis 0 1 (1)
a. All patients were in the PI stratum. 4/5
patients experienced gt1 NSS AE NSS AE (number of
patients) were headache (1), dizziness (3),
insomnia (2), somnolence (1), personality change
(1), mood disturbance (2). 8/10 NSS AE were Grade
2 (moderate), 2/10 (dizziness, headache) were
Grade 3 (severe) b. 1 patient had baseline Scr
2.4 mg/dL and discontinued at Week 6 with Scr
2.3 mg/dL 1 patient had baseline Scr 1.4 mg/dL
and discontinued at Week 21 with Scr 1.3 mg/dL.
Neither patient experienced a Scr elevation while
on study in excess of their baseline value
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Young B, et al., Glasgow 2008
Poster P061
52
Patient Preference Studies
  • Study AI266073
  • ADONE

ATRIPLA is not indicated for treatment-naïve
patients in the EU
53
Study AI266073 Methods
  • The following patient reported outcomes were
    collected in both treatment arms
  • Adherence by Visual Analog Scale
  • Quality of Life (QOL) by SF-36 (v2) survey
  • HIV Symptoms Index by a 20-item survey
  • Perceived Ease of the Regimen for Condition
    (PERC) questionnaire
  • In the Atripla arm only, a Preference of
    Medication (POM) questionnaire was completed

Hodder S et al, P 063, HIV 9, Glasgow 2008
ATRIPLA is not indicated for treatment-naïve
patients in the EU
54
HIV Symptoms Index Statistically Significant
Improvements in Patients Randomised to
EFV/FTC/TDF
PRIOR PI STRATUM
OVERALL




Percent experiencing HIV-related symptom
(p 0.002) (p
0.002) (p 0.002)
(p 0.032)
HIV Symptom Indices
p-values compare change from baseline to Week 48
in patients switched to EFV/FTC/TDF
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Hodder S et al, P 063, HIV 9,
Glasgow 2008
55
HIV Symptoms Index Proportion of Patients
Reporting Dizziness Lightheadedness
50

46
45

39
40
35
32
35
32
30
30
30
30
27
26
28
25
28
Percent Experiencing Symptoms of Dizziness or
Lightheadedness
25
26
24
24
24
23
20
EFV/FTC/TDF Overall
15
16
EFV/FTC/TDF (prior NNRTI)
10
EFV/FTC/TDF (prior PI)
5
SBR
0
p lt 0.002 p lt 0.0014
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Hodder S et al, P 063, HIV 9,
Glasgow 2008
56
Perceived Ease of the Regimen for Condition (PERC)
How Easy Did Patients Consider their Regimen?





of patients who considered their regimen "very
easy" to take
n 202 96 199 93
194 93 187 89
178 83 178 86
plt 0.001 p-values compare treatment arms at
each timepoint
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Hodder S et al, P 063, HIV 9,
Glasgow 2008
57
Preference of Medication (POM) Questionnaire in
Patients Randomised to EFV/FTC/TDF
reporting that EFV/FTC/TDF was "much better"
than their previous regimen
n 116 139
146
143
146 n total number of
patients taking the questionnaire
ATRIPLA is not indicated for treatment-naïve
patients in the EU
Adapted from Hodder S et al, P 063, HIV 9,
Glasgow 2008
58
ADONE study Self reported adherence
P 0.042 P 0.042
adherence and 95CI
Doses consumed last month
Doses consumed right time last month
Doses consumed last week
Doses consumed right time last week
Adapted from Maggiolo F et al. HIV9, November
2008, Glasgow. Poster P-167.
ATRIPLA is not indicated for treatment-naïve
patients in the EU
59
ADONE study Conclusions
  • These preliminary data suggest that switching to
    a FDC of TDF/FTC/EFV, even with a small reduction
    in the daily pill burden, may positively affect
    adherence
  • The compact one pill, once-a-day, FDC based HAART
    is well accepted by patients that score it as
    highly preferable in terms of simplicity,
    convenience, tolerability and potency
  • Both the immunological status and well-being of
    patients improve after switching to the
    simplified, FDC-based HAART

ATRIPLA is not indicated for treatment-naïve
patients in the EU
Maggiolo F et al. HIV9, November 2008, Glasgow.
Poster P-167.
60
Thank you
  • Questions

61
REYATAZ HARD CAPSULES PRESCRIBING
INFORMATION See summary of product
characteristics prior to prescribing
PRESENTATION Hard capsules 150mg, 200mg, 300mg
atazanavir. INDICATION Antiretroviral
combination treatment of HIV-1 infected, adults.
DOSAGE AND ADMINISTRATION Oral. 300mg with
ritonavir 100mg once-daily with food. If
co-administered with didanosine, recommend
didanosine be taken two hours after Reyataz with
ritonavir with food. Hepatic impairment use
caution in patients with mild hepatic
insufficiency. CONTRAINDICATIONS
Hypersensitivity to atazanavir or any excipient.
Moderate to severe hepatic insufficiency. Do not
use in combination with rifampicin or products
that are substrates of CYP3A4 and have a narrow
therapeutic windows or products containing St.
Johns wort. SPECIAL WARNINGS AND PRECAUTIONS
Patients with chronic hepatitis B or C treated
with combination antiretroviral therapy are at
increased risk for severe and potentially fatal
hepatic adverse events. Patients with
pre-existing liver dysfunction must be monitored
according to practice. In worsening liver disease
consider interruption or discontinuation of
treatment. Reyataz may induce PR prolongations.
Caution with medicines that may increase QT
interval. Caution in haemophiliac patients.
Combination antiretroviral therapy has been
associated with lipodystrophy and metabolic
abnormalities. In clinical studies, Reyataz (with
or without ritonavir) has been shown to induce
dyslipidemia to a lesser extent than comparators.
Hyperbilirubinaemia has occurred in patients
receiving Reyataz no dose reduction is
recommended. Nephrolithiasis has been reported in
patients receiving Reyataz. If signs or symptoms
occur, temporary interruption or discontinuation
of treatment may be considered. On initiation of
combination therapy immune reactivation syndrome
may occur.
  • DRUG INTERACTIONS Co-administration of REYATAZ
    with the following agents is not recommended
    simvastatin, lovastatin, nevirapine efavirenz or
    proton pump inhibitors Oral contraceptives Use
    with oral contraceptives should be avoided.
  • Co-administration of REYATAZ/ritonavir is not
    recommended for the following unless justified by
    the benefit/risk ratio voriconazole fluticasone
    or other glucocorticoids that are metabolized by
    CYP3A4. PREGNANCY AND LACTATION Avoid use in
    pregnancy and lactation. UNDESIRABLE EFFECTS
    Common nausea, headache, ocular icterus,
    vomiting, diarrhoea, dyspepsia, abdominal pain,
    jaundice, insomnia, asthenia, peripheral
    neurologic symptoms, rash, fatique and
    lipodystrophy Serious pancreatitis, myopathy,
    hepatitis, nephrolithiasis. LABORATORY
    ABNORMALITIES Elevated bilirubin, creatinine
    kinase LEGAL STATUS POM. PACKAGE QUANTITIES AND
    BASIC NHS PRICE Carton of 60 hard capsules,
    150mg 303.38, 200mg 303.38, carton of 30
    capsules, 300mg 303.38 MARKETING AUTHORISATION
    NUMBERS EU/1/03/267/003 - 150mg Bottle
    EU/1/03/267/005 - 200mg Bottle. EU/1/03/267/008
    -300mg Bottle
  • MARKETING AUTHORISATION HOLDER Bristol-Myers
    Squibb Pharma EEIG, BMS House, Uxbridge Business
    Park, Sanderson Road, Uxbridge, Middlesex. UB8
    1DH. Telephone 0800-731-1736. DATE OF PI
    PREPARATION January 2009
  • REY/0109/2630

Adverse events should be reported. Reporting
forms and information can be found at
www.yellowcard.gov.uk. Adverse events should
also be reported to Bristol-Myers Squibb
Pharmaceuticals Ltd Medical Information on 0800
731 1736, medical.information_at_bms.com
62
SUSTIVA 600mg FILM-COATED TABLETS PRESCRIBING
INFORMATION See Summary of Product
Characteristics prior to prescribing
  • CYP3A4. Other compounds that are substrates of
    CYP3A4 may have decreased plasma concentrations
    when co-administered with efavirenz. Efavirenz
    exposure may alter when given with medicinal
    products or foods (e.g. grapefruit) which affect
    CYP3A4 activity (see Contraindications above).
    See SPC for full drug interaction details for
    protease inhibitors, NRTIs, NNRTIs,
    anticonvulsants, lipid-lowering agents, antacids,
    methadone, St.John's Wort, antidepressants, the
    H1-antihistamine cetirizine, lorazepam,
    antimicrobial and antifungal agents, (efavirenz
    dose should be reduced when co-administered with
    voriconazole and increased when co-administered
    with rifampicin). Potential of interaction with
    oral contraceptives has not been fully
    characterised. PREGNANCY AND LACTATION Avoid use
    in pregnancy and lactation. Barrier contraception
    should always be used in combination with other
    methods of contraception. UNDESIRABLE EFFECTS
    Common rash, pruritus, anxiety, depression,
    nervous system symptoms, psychiatric symptoms,
    immune reactivation syndrome, gastrointestinal,
    skin and subcutaneous tissue disorders, fatigue.
    Serious Stevens-Johnson syndrome, lipodystrophy
    and metabolic abnormalities, acute hepatitis,
    acute pancreatitis. Laboratory abnormalities for
    liver enzymes, amylase, lipids, and false
    positive cannabinoid test results. See SPC for
    full details of side effects. LEGAL STATUS POM.
    PACKAGE QUANTITIES AND BASIC NHS PRICE Blister
    packs of 30 tablets 200.27. MARKETING
    AUTHORISATION NUMBERS EU/1/99/110/009. MARKETING
    AUTHORISATION HOLDER Bristol-Myers Squibb Pharma
    EEIG, BMS House, Uxbridge Business Park,
    Sanderson Road, Uxbridge, Middlesex. UB8 1DH
    Telephone 0800-731-1736. DATE OF PI PREPARATION
    February 2009
  • SUS/0209/2280
  • PRESENTATION Film-coated tablets 600mg
    efavirenz. INDICATIONS Antiretroviral
    combination treatment of HIV-1 infected adults,
    adolescents and children 3 years of age and
    older. Sustiva has not been adequately studied in
    advanced HIV disease. DOSAGE AND ADMINISTRATION
    Oral. Sustiva must be given in combination with
    other antiretroviral medications. Adults and
    adolescents over 40kg 600mg once daily
    preferably at night and on an empty stomach.
    CONTRAINDICATIONS Hypersensitivity to contents.
    Severe hepatic impairment (Child Pugh Grade C).
    Do not use in combination with St. Johns wort or
    products that are substrates of CYP3A4 See SPC
    for details. WARNINGS AND PRECAUTIONS Not for
    sole use. Co-administration of efavirenz with
    Atripla is not recommended. Discontinue use if
    severe rash associated with blistering,
    desquamation, mucosal involvement or fever
    develops. Advise immediate contact with doctor if
    experience severe depression, psychosis or
    suicidal ideation. Nervous system symptoms
    generally resolve after the first 2 - 4 weeks.
    Immune reactivation syndrome may arise with
    severe immune deficiency. Given lipodystrophy
    association with combination antiretroviral
    therapy, consider monitoring fasting serum lipids
    and blood glucose and manage as appropriate.
    Patients with hereditary disorders of
    galactosaemia or glucose/galactose malabsorption
    syndrome should not take Sustiva. Caution needed
    in mild to moderate liver disease or chronic
    Hepatitis B or C infection. Where evidence of
    worsening liver disease, interruption or
    discontinuation of treatment must be considered.
    Close safety monitoring is recommended in
    patients with severe renal failure. Caution if
    history of seizures. DRUG INTERACTIONS Efavirenz
    is an inducer of CYP3A4 and an inhibitor of some
    CYP isozymes including

Adverse events should be reported. Reporting
forms and information can be found at
www.yellowcard.gov.uk. Adverse events should
also be reported to Bristol-Myers Squibb
Pharmaceuticals Ltd Medical Information on 0800
731 1736, medical.information_at_bms.com
63
ZERIT PRESCRIBING INFORMATION Summary of Product
Characteristics prior to prescribing
UNDESIRABLE EFFECTS Common Diarrhoea, nausea,
abdominal pain, dyspepsia, fatigue, lipoatrophy,
lipodystrophy, peripheral neuropathy and other
peripheral neurologic symptoms, dizziness,
headache, insomnia, abnormal dreams, depression,
rash, and pruritus. Less commonly, pancreatitis,
hepatitis, liver failure or jaundice, lactic
acidosis, gynaecomastia, immune reactivation
syndrome, metabolic abnormalities, vomiting,
asthenia, anorexia, arthralgia, myalgia, anxiety,
emotional lability, urticaria, laboratory
abnormalities, motor weakness, mitochondrial
dysfunction. LEGAL STATUS POM PACK QUANTITY
BASIC NHS PRICE Packs of 56 capsules, 20mg
142.28, 30mg 149.20, 40mg 153.70. Powder
for Oral Solution 200ml 23.40 per pack.
MARKETING AUTHORISATION NUMBERS
EU/1/96/009/004(20mg), EU/1/96/009/006 (30mg),
EU/1/96/009/008(40mg), EU/1/96/009/009 (Powder
for Oral Solution). MARKETING AUTHORISATION
HOLDER Bristol-Myers Squibb Pharma EEIG,
Uxbridge Business Park, Sanderson Road, Uxbridge,
Middlesex UB8 1DH. For further information
free-phone 0800-731-1736. DATE OF PI
PREPARATION May 2009. Further information is
available on request from Bristol-Myers Squibb
Pharmaceuticals Ltd., Bristol-Myers Squibb House,
Uxbridge Business Park, Sanderson Road, Uxbridge,
Middlesex UB8 1DH. Telephone 0800-731-1736. HIV/0
509/2893
  • PRESENTATION Capsules 20mg, 30mg, or 40mg
    stavudine. Powder for Oral Solution 200mg.
    INDICATIONS Antiretroviral combination treatment
    of HIV infected patients. DOSAGE Oral, at least
    an hour before a meal, or, if not possible, with
    a light meal. Adults lt60kg - 30mg twice daily,
    60kg - 40mg twice daily. Adolescents, children
    and infants birth to 13 days old - 0.5 mg/kg
    twice daily at least 14 days old and lt 30 kg -
    1mg/kg twice daily patients ?30kg - adult
    dosing. Patients with renal impairment - see SPC.
    CONTRAINDICATIONS Hypersensitivity to any of the
    constituents. WARNINGS PRECAUTIONS Patients
    with a history of peripheral neuropathy,
    pancreatitis or liver disease should be closely
    monitored. Lactic acidosis, sometimes fatal,
    usually associated with hepatomegaly and hepatic
    steatosis has been reported after a few or
    several months treatment and should be closely
    monitored. Children exposed in-utero or
    post-natally to nucleoside analogues should be
    fully investigated for possible mitochondrial
    dysfunction. Lipodystrophy has been linked with
    combination antiretroviral therapy. Immune
    reactivation syndrome may arise in patients with
    severe immune deficiency at time of institution
    of combination antiretroviral therapy (see SPC).
    Unsuitable for individuals with rare hereditary
    problems of galactose intolerance, the Lapp
    lactase deficiency or glucose-galactose
    malabsorption. DRUG INTERACTIONS Other drugs
    actively secreted by renal tube e.g.
    trimethoprim. Use of stavudine in combination
    with zidovudine is not recommended. In vitro
    studies indicate activation of stavudine is
    inhibited by doxorubicin and ribavirin. PREGNANCY
    LACTATION Use should be considered only if
    clearly indicated and only when the potential
    benefit outweighs the possible risk. Women taking
    stavudine should not breast feed. Lactic
    acidosis, sometimes fatal, has been reported in
    pregnant women.

Adverse events should be reported. Reporting
forms and information can be found
at www.yellowcard.gov.uk. Adverse events should
also be reported to Bristol-Myers Squibb
Pharmaceuticals Ltd Medical Information on 0800
731 1736, medical.information_at_bms.com
64
VIDEX EC PRESCRIBING INFORMATION Please refer to
Summary of Product Characteristics prior to
prescribing
  • PRESENTATION Gastro-resistant hard capsules
    125mg, 200mg, 250mg or 400mg didanosine.
    INDICATIONS Antiretroviral combination treatment
    of HIV-1 infected adults, adolescents or children
    over 6 years. DOSAGE Oral. Administer once or
    twice daily at least 2 hours before or after a
    meal with 100ml of water. Adults Recommended
    daily dose 400mg for patients weighing ?60kg and
    250mg for patients weighing lt60kg. Children (over
    6 years) recommended daily dose based on body
    surface area is 240mg/m2 (180mg/m2 in combination
    with zidovudine). Dose adjustment required for
    patients with renal impairment. Refer to SPC for
    full details. CONTRAINDICATIONS
    Hypersensitivity to contents. Children younger
    than 6 years. SPECIAL WARNINGS AND PRECAUTIONS
    Not for sole use. Extreme caution in patients
    with history of pancreatitis. Where possible
    suspend dosing until a diagnosis of pancreatitis
    has been excluded and when treatment with other
    drugs known to cause pancreatic toxicity is
    required, suspend didanosine wherever possible.
    Dose suspension should be considered when
    biochemical markers of pancreatitis have
    increased, even in the absence of symptoms.
    Patients on didanosine may develop toxic
    peripheral neuropathy. Suspend Videx EC until
    resolution of symptoms. A reduced dose may then
    be tolerated. Liver failure has occurred rarely.
    Observe for liver enzyme elevations and suspend
    treatment if enzymes rise gt5 times above the
    upper limit of normal. Re-challenge only if the
    potential benefits clearly outweigh the potential
    risks. Lactic acidosis has been reported with the
    use of nucleoside analogues. Retinal or optic
    nerve changes may occur rarely. Children should
    have a retinal examination every 6 months or if a
    change in vision occurs. Given lipodystrophy
    association with combination antiretroviral
    therapy, consider monitoring fasting serum lipids
    and blood glucose and manage as appropriate.
    Nucleoside and nucleotide analogues have been
    reported to cause mitochondrial dysfunction in
    HIV-negative infants exposed in-utero and/or
    post-natally. DRUG INTERACTIONS
    Co-administration with drugs known to cause
    peripheral neuropathy or pancreatitis may
    increase the risk of these toxicities.
  • Co-administration of didanosine and tenofovir
    disoproxil fumarate results in a 40-60 increase
    in systemic exposure to didanosine and is
    therefore not recommended. Co-administration of
    didanosine with xanthine oxidase inhibitors, such
    as allopurinol, may result in increased systemic
    exposure to didanosine, therefore patients should
    be carefully monitored for didanosine-related
    adverse events.
  • PREGNANCY LACTATION Avoid use in pregnancy and
    lactation. Use only when the potential benefit
    outweighs the possible risk. UNDESIRABLE
    EFFECTS Common Pancreatitis, peripheral
    neurologic symptoms, lipodystrophy and metabolic
    abnormalities, diarrhoea, nausea, vomiting,
    abdominal pain, rash, fatigue, allergic
    reactions, asthenia, headache, neutropenia.
    Increased uric acid, liver enzymes, bilirubin
    level. Rarely reported events post marketing are
    chills and fever, flatulence, parotid gland
    enlargement, dry mouth, lactic acidosis,
    anorexia, diabetes mellitus, hypoglycaemia,
    hyperglycaemia, alopecia, hepatitis, liver
    failure, hepatic steatosis, sialoadenitis,
    anaemia, leukopenia, thrombocytopenia,
    anaphylactic reaction, dry eyes, retinal
    depigmentation, optic neuritis, myalgia,
    rhabdomyolysis. LEGAL STATUS POM. PACK QUANTITY
    BASIC NHS PRICE Blister packs of 30 capsules
    125mg 49.16, 200mg 78.65, 250mg 98.31,
    400mg 157.30 MARKETING AUTHORISATION NUMBERS
    11184/0083 125mg, 11184/0084 200mg, 11184/0085
    250mg, 11184/0086 400mg. MARKETING AUTHORISATION
    HOLDER Bristol-Myers Squibb Pharmaceuticals
    Limited, Uxbridge Business Park, Sanderson Road,
    Uxbridge, Middlesex UB8 1DH. DATE OF PI
    PREPARATION May 2009. Further information is
    available on request from Bristol-Myers Squibb
    Pharmaceuticals Ltd., Bristol-Myers Squibb House,
    Uxbridge Business Park, Sanderson Road, Uxbridge,
    Middlesex UB8 1DH. Telephone 0800-731-1736.
  • HIV/0509/2892

Adverse events should be reported. Reporting
forms and information can be found at
www.yellowcard.gov.uk. Adverse events should
also be reported to Bristol-Myers Squibb
Pharmaceuticals Ltd Medical Information on 0800
731 1736, medical.information_at_bms.com
65
ATRIPLA PRESCRIBING INFORMATION
blood glucose and manage lipid disorders as
appropriate. Other Administration of Atripla
with food may increase efavirenz exposure.
Mitochondrial dysfunction. Immune Reactivation
Syndrome. Osteonecrosis. Decreased bone mineral
density and bone abnormalities (infrequently
contributing to fractures), which may be
associated with proximal renal tubulopathy.
Co-administration of Atripla and didanosine is
not recommended as exposure to didanosine is
significantly increased. Avoid in antiretroviral
experienced patients with strains harbouring
K65R, M184V/I or K103N mutations. Contains sodium
consider in patients on sodium-restricted
diet. Interactions Efavirenz is an inducer of
CYP3A4 and an inhibitor of some CYP450 isoenzymes
including CYP3A4. Other compounds that are
substrates of CYP3A4 may have decreased plasma
concentrations when co-administered with
efavirenz. Efavirenz exposure may also be altered
when given with medicinal products or foods (e.g.
grapefruit juice) which affect CYP3A4 activity
see contraindications above. Atripla should not
be co-administered with adefovir dipivoxil,
lamivudine, atazanavir/ritonavir or didanosine.
Avoid co-administration of Atripla with medicinal
products that reduce renal function or compete
for active tubular secretion (e.g. cidofovir).
Avoid use of Atripla with concurrent or recent
use of nephrotoxic medicinal product. Refer to
SPC for drug interaction details for protease
inhibitors, NRTIs, NNRTIs, antimicrobial and
antifungal agents, anticonvulsants,
antidepressants, cardiovascular agents,
lipid-lowering agents, hormonal contraceptives,
opioids and herbal products. Use in pregnancy
and lactation Atripla should not be used in
pregnancy unless clearly necessary. Barrier
contraception should always be used in
combination with other methods of contraception.
Avoid breast-feeding. Side effects Very
commonly reported adverse events (1/10)
dizziness, headache, diarrhoea, nausea, vomiting,
elevated creatine kinase, rash (all grades),
hypophosphataemia. Commonly reported adverse
events (1/100, lt1/10) anorexia, neutropenia,
stupor, lethargy, disturbance of attention
somnolence, dyspepsia, abdominal pain and
distension, flatulence, dry mouth, elevated serum
lipase, elevated amylase including elevated
pancreatic amylase, allergic reaction, pruritus,
maculopapular rash, urticaria, vesiculobullous
rash, pustular rash, skin hyperpigmentation,
dermatitis, night sweats, blood creatinine
increased, increased energy, decreased or
increased appetite, hypertriglyceridaemia,
hyperglycaemia, hot flush, fatigue, fever, pain,
asthenia, hyperbilirubinaemia, increased AST and
ALT, anxiety, depression (including severe),
nightmares, abnormal dreams, insomnia, sleep
disorder, altered mood (euphoric or depressed),
vertigo. Uncommonly reported adverse events
(1/1,000, lt1/100) Stevens-Johnson syndrome,
erythema multiforme, suicide ideation (except in
patients with a history of psychiatric
disorders), acute pancreatitis and acute
hepatitis. Refer to SPC for full list. Adverse
events of unknown frequency renal failure (acute
and chronic), acute tubular necrosis, proximal
tubulopathy including Fanconi syndrome, nephritis
(including acute interstitial nephritis),
nephrogenic diabetes insipidus, proteinuria,
photoallergic dermatitis, rhabdomyolysis,
osteomalacia (manifested as bone pain and
infrequently contributing to fractures), muscular
weakness, myopathy, osteonecrosis (particularly
in patients with generally acknowledged risk
factors, advanced HIV disease or long-term
exposure to CART), lactic acidosis,
hypokalaemia, hepatitis, hepatic steatosis,
hepatic failure, completed suicide, psychosis,
neurosis, cerebellar coordination and balance
disturbances. The side effects marked may occur
as a consequence of proximal renal tubulopathy.
Combination antiretroviral therapy has been
associated with metabolic abnormalities including
hypercholesterolaemia, insulin-resistance and
hyperlactataemia as well as lipodystrophy. HIV
patients with severe immunodeficiency at the time
of initiation of CART may experience Immune
Reactivation Syndrome. Refer to SPC for further
information on adverse events. Overdosage If
overdosage occurs, monitor for evidence of
toxicity. Apply standard supportive treatment if
necessary. Emtricitabine and tenofovir, but not
efavirenz, can be removed by haemodialysis.
Administration of activated charcoal may be used
to aid removal of unabsorbed efavirenz. Pharmaceut
ical Precautions No special requirements for use
and handling. Store in the original package in
order to protect from moisture. Keep the bottle
tightly closed. Legal Category POM. Package
Quantities Bottle of 30 film-coated tablets.
Price UK NHS 626.90. Marketing Authorisation
Number EU/1/07/430/001. The Marketing
Authorisation Holder is Bristol-Myers Squibb and
Gilead Sciences Limited, Unit 13, Stillorgan
Industrial Park, Blackrock, Co. Dublin, Ireland.
Further information is available from the local
representative of the Marketing Authorisation
Holder Gilead Sciences International Ltd,
Flowers Building, Granta Park, Abington, Cambs,
CB21 6GT. Telephone 01223 897555. e-mail
ukmedinfo_at_gilead.com CONSULT THE SUMMARY OF
PRODUCT CHARACTERISTICS BEFORE PRESCRIBING
PARTICULARLY IN RELATION TO SIDE EFFECTS,
PRECAUTIONS AND CONTRAINDICATIONS. Atripla is a
registered trademark


Date of PI Preparation April 2009.
177/UKM/09-04/SM/1052 Atripla PI version April
09
ATRIPLA PRESCRIBING INFORMATION Presentation
Atripla film-coated tablet. Each tablet contains
600mg of efavirenz, 200mg of emtricitabine and
245mg of tenofovir disoproxil (as fumarate).
Indications For treatment of HIV-1 infected
adults with virologic suppression to HIV-1 RNA
levels of lt50 copies/ml on their current
combination therapy for more than 3 months.
Patients must not have experienced virological
failure on prior antiretroviral therapy and must
not have resistance to any of the three
components of Atripla. Dosage Administration
Therapy should be initiated by a physician
experienced in the management of HIV infection.
Adults One tablet once daily taken orally on an
empty stomach at bedtime. Children and
adolescents not recommended. Elderly
Insufficient data are available on which to make
dose recommendations for patients over the age of
65 years caution should be exercised. Not
recommended in patients with moderate or severe
renal impairment (CrCl lt50ml/min). No dose
modification necessary in patients with mild to
moderate liver disease. Contraindications
Hypersensitivity to efavirenz, emtricitabine,
tenofovir, tenofovir disoproxil fumarate, or any
of the excipients. Atripla must not be used in
patients with severe hepatic impairment. It must
not be administered concurrently with
terfenadine, astemizole, cisapride, midazolam,
triazolam, pimozide, bepridil or ergot alkaloids,
because competition for CYP3A4 by efavirenz could
result in inhibition of metabolism and create the
potential for serious and/or life-threatening
undesirable effects (e.g. cardiac arrhythmias,
prolonged sedation or respiratory depression).
Herbal preparations containing St. Johns wort
must not be used while taking Atripla due to the
risk of decreased plasma concentrations and
reduced clinical effects of efavirenz. Atripla
must not be administered concurrently with
voriconazole because efavirenz significantly
decreases voriconazole plasma concentrations,
while voriconazole significantly increases
efavirenz plasma concentrations. Warnings and
Precautions Atripla should not be administered
concomitantly with other medicinal products
containing any of the same active components,
with other cytidine analogues such as lamivudine
or with adefovir dipivoxil. Patients switched to
Atripla from a PI-based regimen may have a
reduced response to therapy monitor viral load
and adverse reactions. Appropriate precautions
must be used to prevent the risk of transmission
of HIV to others through sexual contact or
contamination with blood. Hepatic Discontinue
Atripla in patients developing symptomatic
hyperlactataemia, metabolic/lactic acidosis,
progressive hepatomegaly or rapidly elevating
aminotransferase levels. Use with caution in
patients with hepatomegaly, hepatitis, other risk
factors for liver disease and hepatic steatosis,
co-infection with HCV and treatment with alpha
interferon and ribavirin monitor closely.
Caution in administering Atripla to patients with
mild or moderate liver disease. Patients with
pre-existing liver dysfunction should be
monitored interruption or discontinuation of
treatment must be considered if evidence of
worsening liver disease or persistent elevations
of serum transaminases gt5 times ULN. HBV
Co-infection Patients with HIV co-infected with
either HBV or HCV treated with combination
antiretroviral therapy are at increased risk of
severe and potentially fatal hepatic adverse
reactions. Discontinuation of therapy may be
associated with severe acute exacerbations of
hepatitis. Co-infected HIV/HBV patients should be
closely monitored for at least four months
following discontinuation of Atripla for symptoms
of severe acute exacerbations of hepatitis.
Psychiatric Advise patients to contact their
doctor immediately if they experience psychiatric
symptoms such as severe depression, psychosis or
suicidal ideation. Nervous system symptoms such
as dizziness, insomnia, somnolence, impaired
concentration and abnormal dreams may begin
during the first 1 or 2 days of therapy and
generally resolve after the first 2 - 4 weeks.
Exercise caution in any patient with a history of
seizures. Renal Atripla is not recommended for
patients with moderate or severe renal
impairment. Avoid use of Atripla with concurrent
or recent use of nephrotoxic medicinal product.
If concomitant use of Atripla with a nephrotoxic
agent is unavoidable, monitor renal function
weekly. Renal failure and impairment, elevated
creatinine, hypophosphataemia and proximal
tubulopathy (including Fanconi syndrome) have
been reported with use of tenofovir disoproxil
fumarate in clinical practice. It is recommended
that CrCl is calculated in all patients prior to
therapy initiation and renal function monitored
every 4 weeks for the first year and every 3
months thereafter. In patients at risk of renal
impairment, consideration should be given to more
frequent monitoring of renal function. If CrCl is
decreased to lt50ml/min or serum phosphate is
decreased to lt1.5mg/dl, renal function should be
re-evaluated within one week. Treatment with
Atripla should be interrupted if CrCl is
confirmed to be lt50ml/min or if serum phosphate
is decreased to lt1mg/dl. Refer to SPC for further
recommendations regarding monitoring, dose
adjustment and discontinuation of therapy. Skin
reactions Discontinue Atripla in patients who
develop severe rash associated with blistering,
desquamation, mucosal involvement or fever.
Lipodystrophy and metabolic Combination
antiretroviral therapy has been associated with
lipodystrophy in HIV patients. Consider
monitoring fasting serum lipids and
Adverse events should be reported. Reporting
forms and information can be found at
www.yellowcard.gov.uk. Adverse events should also
be reported to Bristol Myers Squibb
Pharmaceuticals Ltd Medical Information on
08007311736 or medical.information_at_bms.com
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