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 BMS Virology Portfolio VIdex® Didanosine (ddI) Zerit® stavudine (D4T) DDI and D4T safety update Topics • Peripheral neuropathy • CV risk • Hepatotoxicity
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BMS Data Update - UK-CAB · 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
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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
BMS Virology Portfolio
VIdex®
Didanosine (ddI)
Zerit®
stavudine (D4T)
DDI and D4T safety update
Topics
• Peripheral neuropathy
• CV risk
• Hepatotoxicity
2
Peripheral neuropathy Study 903 % Patients < 50 Copies/mL
% P
atie
nts
with
HIV
-1 R
NA
< 50
c/m
L Weeks
73% 69%
Intent to Treat (Missing=Failure)
TDF+3TC+EFV d4T+3TC+EFV
Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201
Study 903 Selected Toxicities Associated with Mitochondrial Dysfunction through Week 144
Kovari et al Clinical infectious diseases 2009:49 626-635
Literature review of noncirrhotic portal hypertension
Kovari et al Clinical infectious diseases 2009:49 626-635
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 2009:49 626-635
Definition of NCPH in this study
• Endoscopically confirmed varices
• Presenting symptoms include increased liver enzymes, heamatamesis or ascites
Kovari et al Clinical infectious diseases 2009:49 626-635
5
Kovari et al Clinical infectious diseases 2009:49 626-635 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 2009:49 626-635
• 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”
Study Conclusions
Kovari et al Clinical infectious diseases 2009:49 626-635
Naïve patients: BHIVA 2008: What to start with?
A B
NRTI AZT>
ddI
+
aexcept in women who may wish to become pregnant *Only when CD4 <250 cells/mm3 in females, <400 cells/mm3 in males ~ Where established cardiovascular disease risk factors and a PI required > Co-formulated as Combivir® & Co-formulated as Kivexa® + Co-formulated as Truvada®
alternative
C
+
Gazzard et al, HIV Medicine (2008) vol 9 563-608
6
ACTG 5142 Study: Co-Primary Endpoint: Time to Virologic Failure (VF)
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. 2008;358:2095-2106.
Number of Patients 0 24 48 72 96 120 144
Weeks After Randomization
EFV + 2 NRTIs vs LPV/r + 2 NRTIs : P=0.006 EFV + LPV/r vs EFV + 2 NRTIs : P=0.49 (NS) EFV + LPV/r vs LPV/r + 2 NRTIs: P=0.13 (NS) (threshold for significance P<0.014)
100
90
80
70
60
50
40
30
Prob
abili
ty o
f no
Viro
logi
c Fa
ilure
(%) EFV + 2 NRTIs
LPV/r + 2 NRTIs EFV + LPV/r
║
0
║
EFV + 2 NRTIs arm had a statistically significantly longer time to virologic failure than the LPV/r + 2 NRTIs arm
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
d4t BID
EFV QD
3TC BID
TDF placebo QD
TDF QD
EFV QD
3TC QD
(OPEN-LABEL)
Study 903 3 Years (144 Weeks)
Study 903E
7 Years (336 Weeks)
n = 86
Adapted from Madruga JVR, et al , ICDT 2008, Poster P4
903E Study: HIV-1 RNA, CD4, and Resistance
Resistance • 4 patients discontinued due to virologic
Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136
39
Grade 2–4 treatment-related AEs through Week 48: As-treated patients, n (%)
Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136
• 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
ATV/r LPV/r
HBV/HCV−
(n=380)
HBV/HCV+
(n=60)
HBV/HCV−
(n=385)
HBV/HCV+
(n=51)
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 (<1) 0
Jaundice 16 (4) 2 (3) 0 0
40 1. Lapadula G, et al. EACS 2007, Poster 9.6/03; 2. Lankisch TO, et al. Hepatology 2006;44:1324–1332, 3. http://www.emea.europa.eu/humandocs/Humans/EPAR/reyataz/reyataz.htm
• 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 Gilbert’s 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
11
41 Egger M, 14th CROI, 2007, Abstract 62. ART Cohort Collaboration http://www.art-cohort-collaboration.org
2003–2005
• 42 countries, 176 sites, 33 008 patients
• Low CD4 count at start of treatment suggests that many patients have advanced disease
42
0 10 20 30 40 50 60 70 80 90
100
ATV/r LPV/r
HIV RNA <100 000 copies/mL
HIV RNA ≥100 000 copies/mL
75 70 74
66
Res
pond
ers
(%) <
50 c
/mL
Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008, Poster H-1250d
ITT-confirmed virological response (NC=F) at Week 96 by qualifying HIV viral load
n=225 n=218 n=223 n=217
43
76 71 71
78
69 70 69
58
ATV/r LPV/r n= 222 106 45 58 228 134 29 48
Res
pond
ers
(%) <
50 c
/mL
Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d
p=ns p=ns
50–<100 cells/mm3
<50 cells/mm3
Treatment Experienced patients
1. Hammer SM, et al. JAMA. 2006;296:827-843. 2. BHIVA website: http://www.bhiva.org/files/file1030835.pdf (Pre-press version of 2008 BHIVA Guidelines for HIV Anti-Retroviral Treatment; on page 11-Accessed on 04 September 2008)
12
Evolution of Once-daily ATRIPLA® Dosing
Sustiva SmPC, September 2008 Viread SmPC, September 2008 Emtriva SmPC, September 2008 Truvada SmPC, December 2008 ATRIPLA SmPC, December 2008
Efavirenz (Sustiva®)
Emtricitabine (Emtriva®)
Tenofovir DF (Viread®)
Truvada®
ATRIPLA®
The pills shown are not the actual size
The ATRIPLA® Indication in Europe
ATRIPLA SmPC
• 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 <50 copies/mL on their current combination antiretroviral therapy for >3 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
Efficacy of ATRIPLA® Study AI266073 Design
• Stable ARV Regimen
(PI or NNRTI + 2 NRTIs) for ≥ 3 months
• VL <200 copies/mL
• No History of Virologic Failure
EFV/FTC/TDF Once Daily
Stayed on Baseline Regimen*
*SBR: stayed on baseline regimen
Switch
Continue
Primary Endpoint: assess non-inferiority of EFV/FTC/TDF vs. SBR in terms of maintenance of HIV-1 RNA <200 copies/mL through Week 48 by TLOVR**analyses
**Time to loss of Virologic Response Algorithm
Phase IV, multicentre (55 US sites), open-label study (N = 300)
Randomisation 2:1
Stratify by PI or NNRTI
0 24 48 Week
Adapted from Young B, et al., Glasgow 2008; Poster #P061 ATRIPLA® is not indicated for treatment-naïve patients in the EU
ARV Baseline Regimen
EFV 36%
NVP 11% ATV/r 15%
LPV/r 13% FPV/r (9%)
SQV/r (2%)
IDV (2%)
NFV (7%)
ATV (2%) FPV (3%)
a. Most frequent NNRTI regimens were: EFV+AZT/3TC (16%), EFV+ABC/3TC (6%), EFV+TDF+3TC (5%) b. Most frequent PI regimens were: ATV/r + FTC/TDF (13%), LPV/r + FTC/TDF (6%), FPV/r+ABC/3TC (4%)
PIs (53%) NNRTIs (47%)
Adapted from DeJesus EACS 2007, Madrid, Spain ATRIPLA® is not indicated for treatment-naïve patients in the EU
13
Primary Endpoint Analysis: Percentage of Patients with HIV-1 RNA <200 copies/mL Through 48 Weeks (TLOVR)
• 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
Efficacy Analysis by Prior Treatment Stratum: Week 48
Stratum at Baseline
Patients Below HIV-1 RNA Threshold (%)
Prior NNRTI Prior PI
EFV/FTC/TDF (N = 95)
SBR (N = 45)
EFV/FTC/TDF (N = 108)
SBR (N = 52)
<200 copies/mL
TLOVRa 92% 84% 87% 90%
M=Eb 100% 100% 100% 100%
<50 copies/mL
TLOVR 92% 82% 83% 87%
M=E 100% 97% 98% 98% a. Time to loss of virologic response algorithm (NC=F) b. Missing data (for any reason) was excluded in this analysis P=NS for all comparisons in both strata
Adapted from Young B, et al., Glasgow 2008; Poster #P061 ATRIPLA® is not indicated for treatment-naïve patients in the EU
Discontinuations Due to Adverse Events
N (%) EFV/FTC/TDF (N=203)
SBR (N=97)
Any Adverse Event 10 (5%) 1 (1%) Nervous system symptoms (NSS)a 5 (2%) 0
Increased creatinineb 2 (<1%) 0
Acute hepatitis 1 (<1%) 0
AST/ALT elevation 1 (<1%) 0
Acute pancreatitis 1 (<1%) 0
Gastritis 0 1 (1%) a. All patients were in the PI stratum. 4/5 patients experienced >1 NSS AE; NSS AE
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
Adapted from Young B, et al., Glasgow 2008; Poster #P061 ATRIPLA® is not indicated for treatment-naïve patients in the EU
Patient Preference Studies
Study AI266073 ADONE
ATRIPLA® is not indicated for treatment-naïve patients in the EU
14
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
HIV Symptoms Index: Statistically Significant Improvements in Patients Randomised to EFV/FTC/TDF
Perc
ent e
xper
iencin
g HI
V-re
lated
sym
ptom
HIV Symptom Indices
*p-values compare change from baseline to Week 48 in patients switched to EFV/FTC/TDF
PRIOR PI STRATUM OVERALL
*
* * *
(p = 0.002) (p = 0.002) (p = 0.002) (p = 0.032)
Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU
HIV Symptoms Index: Proportion of Patients Reporting Dizziness & Lightheadedness
Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU
Perceived Ease of the Regimen for Condition (PERC)
% o
f pat
ients
who
cons
ider
ed th
eir re
gim
en
"ver
y eas
y" to
take
How Easy Did Patients Consider their Regimen?
n = 202 96 199 93 194 93 187 89 178 83 178 86
* = p< 0.001 p-values compare treatment arms at each timepoint
* * * * *
Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU
15
Preference of Medication (POM) Questionnaire in Patients Randomised to EFV/FTC/TDF
n = 116 139 146 143 146 n = total number of patients taking the questionnaire
% re
porti
ng th
at E
FV/F
TC/T
DF w
as "m
uch
bette
r" th
an th
eir p
revio
us re
gim
en
Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU
Doses consumed last month
adh
eren
ce %
and
95%
CI
P = 0.042 P = 0.042
Baseline
1 month post switch
2 months post switch
Doses consumed right time last month
Doses consumed last week
Doses consumed right time last week
ADONE study Self reported adherence
92
93
94
95
96
97
98
99
100
Adapted from Maggiolo F et al. HIV9, November 2008, Glasgow. Poster# P-167. ATRIPLA® is not indicated for treatment-naïve patients in the EU
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
Maggiolo F et al. HIV9, November 2008, Glasgow. Poster# P-167. ATRIPLA® is not indicated for treatment-naïve patients in the EU
Thank you
Questions
16
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
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. John’s 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.
REYATAZ® HARD CAPSULES PRESCRIBING INFORMATION See summary of product characteristics prior to prescribing
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
SUSTIVA® 600mg FILM-COATED TABLETS PRESCRIBING INFORMATION See Summary of Product Characteristics prior to prescribing
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. John’s 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
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
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
ZERIT® PRESCRIBING INFORMATION Summary of Product Characteristics prior to prescribing
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: <60kg - 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 < 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 month’s 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.
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/0509/2893
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
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 <60kg. 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 >5 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
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 <50 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 <50ml/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. John’s 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 >5 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 <50ml/min or serum phosphate is decreased to <1.5mg/dl, renal function should be re-evaluated within one week. Treatment with Atripla should be interrupted if CrCl is confirmed to be <50ml/min or if serum phosphate is decreased to <1mg/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
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, <1/10): 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, <1/100): 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. Pharmaceutical 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: [email protected] 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 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