Final Program [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

Viread
reo d sopr Jmr2 Tablets
The foAlowing is a brief summary: see current package insert for complete information
WARNING
LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL
CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGS ALONE OR
IN COMBINATION WITH OTHER ANTIRETROVIRALS (SE WARNINGS).
INDICATIONS AND USAGE
VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV 1infection This
indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of VIREAD
of 24 weeks duration and in a controlled, dose ranging study of VtREAD of 48 weeks duration. Both studies were
conducted in treatment exprienced adults with evidence of HtV-1 viral replication despite ongoing antiretroviral
therapy. Studies in ant'"etroviral naive patients are ongoing; consequently, the risk-benefit ratiofor this population
has yet to be determine.
CONTRAINDCATIONS
VIREAD is contraindicated in patients with previously demonstrated hypersensitivity to any of the components
of the product
WARNINGS
Lactic Ackiosi/Seer Hepatomegay with Steatosis
Lactic acidosis and severe hpatomegaly with steatosis, including fat caseshave been reported with the use of
nucosideanalogs alone or in combination with other antiretrovirals A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors Particular caution should be exercised when
admistering nucleoside analogs to any patient with known risk factors for liver disease; however cases have also
been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient
who develops dclinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may
include hepatomegaly and steaos even in the absence of marked transaminase eevations).
Renal Impaiment
Tenoovir is principally eliminated by the kidney VIREAD should not be administered to patients with renal
insufficiency (creatinine clearance < 60 mUimin) until data become available describing the disposition of VIREAD
in these patients
PRECAUIONS
or Mwactio
When administered with VIREAD, and AUC of didanos (administered as the buffered formulation) increased by
28% and 44%, respectively The mechanism for this interaction is unknown Although an increased rate of
didanosine-associated adverse events has riot been observed in pooled clinical studies at this time, long term effects
are unknown. Patients og VIREAD and didanosine concomitantly should be monitored for long term didanosineassociated adverse events. (See CLINICAL PHARMACOLOGY Drug Interactions, and DOSAGE ANDADMINISTRATION)
Since tenofovir is primarily eliminated by the kineys, co-administration of VIREAD with drugs tat reduce renal
function or ompete for active tubular secretion may increase serum concentrations of tenoovir and/or increase the
concentrations of other renally eliminated drugs Some examples include, but am not limited to cidofovir, acyclo,
valacyclovir ganciovir, and vaganciclovir.
Hepac kpanent
The pharmacokinetics of tenofovir have not been studied in patients with hepatic impairment. As tenofovir
and tenofovir disoproxit are not metabolized by liver enzymes, the impact of liver impairment should be
limited. However, because tenofovir is not entirely renally excreted (70-80%), tenofovir pharmacokinetics
may be altered in patients with hepatic insufficiency,
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump),
peripheral wasting, facial wasting, breast entlargement and "cushingod appearce" have been observed in
patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are
currently unknown. A causal relationship has not been established.
Animal Toxicoloy
Tenoovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at
exposures (based on ACs) between 6 and 12 fold those observed in humans caused bone toxicity In monkeys the
bone toxic tywas diagnosed as osteomalacia. O ia observed in monkeys appeared to be reversible upon
dose reduction or discontinuation of tenovir In rats and dogs, the bone to*icty manifested as reduced bone
mineral density The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was notedr in 4 animal species. Increases in serum creatinine, BUN, gtycosuria, proteinuria,
phosphaturia and/or calciuria, and decreases in serum phosphate were observed to varying degrees in these
animals These toxicites were noted at exposures (based on AUCs) 2-20 times higher than those observed in
humans The relationshipof the renal abnormalities, particularly the phospaturia, to the bone toxicity is not known.
Clinical Monitoring for Bone and Renal Toxicity
It is not known if long term administation of VIREAD(>1 year) will cause bone abnormalities Therefore if bone
abnormalities are suspected then appopriate consultation should be obtained.
Although tenoovir-associated renal toxicity has not been observed in pooled clinical studies for up to one year,
tong-term renal effects are unknown. Consideration should be given to monitoring for changes in serum creatine
and serum phosphorus in patients at risk or with a history of renal dysfunction.
Carcmogenes, M ns pairment of Fertility
Longterm carcinogenicity studie of tnoovir disoproxi! fumarate in rats an mice are in progress
T r disoproxil fumarate was mntagenic in the in vitro mouse ymphoma assay and negative n an in vitro
bacteri mutagenic'ty (Ames test). In an in viv mouse micronuceus assay. t 'nofvir disoproxi fumarate was
negative at doses up to 2000 mg/kg when administered to male mice
Thre were no eff on fer7i, mating pfmanceo early em onic development en tenoov i roxi t
simarate was admiisee at60m/g/day tomat rat fo 28 day 'ro to matin and totfemal rats Io
15 days prio to mating trough day seven of geslaion. There was, however, an altration of the estous
cycle in female rats. A dose of 600 mgikg/day is equivalent to I0 times the human dose based on body
surface area comparisons.
Pregnancy
Pregnancy categary B: Reprodu'ct~ estieae been performed is rutsand ratblsat doses up to 1 4 and 19
times human dose based on body surace area comp and revealed no evidence of impaired teri or
harm to the fetus due to tenofovi. ere are, however no adequate and we ltoed studies in pregnant women.
Because animal reproduction studies are not always predc of human response, VtIEAD should be used during
pracy My I dearly needed
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to VIREAD, an
Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register
patients by calling 1-800-258-4263.

NMrsing Mothers: The Centers for Disease Control and Prevention recommend that NW-infected mothers
not bre ast-feed their Infant s to a d risking postnatal tran ssion of HN. Studies in rats have demonstrated
that tenoovir is secreted in milk. It is not known whether tenofovir is excreted in human milk Because of both the
potential for HIV ftsmissien and the potential for serious adverse reactions in nursing infants, mothers should be
instructed not to breast-feed if they are receiving VIREAD
Peat diatric Use
Safety and effectiveness in pediatricp a hve not been estaished.

Geriatric Use
Clinical studies of VIREAD did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects In general, dose selection for the elderly patient
should be cautious, keeping in mind the grater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy.
ADVERSE REACTIONIS
More than 1000 patients have been treated with VREAD alone or in combination with other antiretroviral medica
products for periods of 28 days to 143 weeks in Phase -I cinical trials and a compassionate access s y.
Assessment of adverse reactions is based on two studies (902 and 907) in which 653 treatment experienced
patients received double-blind treatment with VIREAD 300 mg (n=443) or placebo (n=210) for
24 weeks followed by extended treatment with VIREAD.
Treatment-Relaed Adverse Events The most common adverse events that occurred in patients receiving
VIREAD witother antiretroviral ages inclinical trials were mild to moderate gasiointst events,
such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of patients disoinued partcipation in the linicat
studies due to gastrointestinal adverse events
A summary of treatment-relate adverse events is provided in Table 1 below.
Table 1. Treatment-Related Adverse Events (Grades 1-4) Reported in 3% of
VIREAD-Treated Patients n the Pooled 902-97 Studles (0-24 weeks)
VIEAD 300 m Placebo
Number of Patients Treated 443 210
Nausea 11% 10%
Diarrhea 9% 8%
Astheni 8% 8%
Headache 6% 7%
Vomiting 5% 2%o
Ratulence 4%1 0%
Abdominal Pain 3% 3%
Anorexia 3% 1%
Laboratory Abnormnaies: Laboratory abnormalities observed in these studies occurred with similar
frequency in the VIREAD and placebo treated groups. A summary of Grade 3 and 4 laboratory abnormalities is
provided in Table 2 below
Table 2. Grade 3/4 Laboratory Abnormalies Reported in 1% of VIREAD-Treated
Patients in the Pooled 902-907W Studies (0-24 weeks)
VIREAD 300 mg Placebo
Number of Patients Treated 443 210
Number of Patients with
Grade 3 or 4 Laboratory 117(26%) 78 (37%)
Abnormalities
Laboratory Abnormalities
Triglycerle (>750 mg/dL) 37 (8%) 28 (13%)
Creatine kinase (>782 U/L) 53 (12%) 38 (18%)
Serum amylase (>175 U/L) 21 (5%) 14 (7%)
AST
(M:>180 U/L) 16(4%) 6(3%)
(F:>170 U/)
Urine glucose (3+ or 4+) 12 (3%) 6 (3%)
ALT elevation
(M: >215 UL) 10 (2%) 4 (2%)
(F: >170 U/L)
Serum glucose (>250 ng/dL) 8 (2%) 8 (4%)
Neutrophil (<650/mm). 6 (1%) 3 (11%)
OVERDOSAGE
Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study
901 tenofovir disoproxil fumarate 600 mg was administered to 8 patients orally for 28 days. No severe adverse
reactions were reported. The effects of higher doses are not known
If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment
applied as necessary
It is not known whether peritoneal dialysis or hemodialysis increases the rate of elimination of tenofovir.
DOSAGE AND ADMINISTRATION
The dose of VEAD (teovir disoproxil fumarate) is 300 mg e daily taken orally with a meal
Concomitant administration: Didanosine Wh en administered with didanosine, VREADshould be administered
2 hours 1eor c one hortr administation it' diosine (See PRECAUTIONS, Drug Intractions).
lOW U ED
VREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equo int
to 245 mg of tenofovir disoproxi. The tablets are almond shaped, light blue film-coated, and debossed with
'GILEAD' nd331"oneside and w 300 the oer sideThey aepaaged asfollows: Bottles
at 30 tbets (NDC 61958-0401-1) otamning a dsiccant (sitica get canister orsachet) and closed i'
child-resstant closure.
Store at 25~C (/?F), excuisions permitted to 15-3(?C (59-86 F) (see USP Controlled Room Temperature).
Gilead Sciences, Inc.
Foster City CA 94404

April 2002
VIREAD is a trademark of Gilead Sciences, Inc.
~ 2002 Gilead Sciences, Inc.

GILEAD