R

A
E
DV
I M
T (Tenofovir Disoproxil Fumarate 200 mg)

1. INDICATIONS AND USAGE

VIREAD ® is indicated in combination with other antiretroviral agents for the treatment HIV-1 infection as a second line
treatment.
The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:
• VIREAD should not be administered with a n v other medicinal products containing tenofovir disoproxil fumarate [See
Warnings and Precautions (5.4)].

2. DOSAGE AND ADMINISTRATION

1.2 Recommended Dose

For the treatment of HIV-1: The dose of VIREAD is 300 mg once daily taken orally, without regard to food.

2 . 2 Dose Adjustment for Renal Impairment

Significantly increased drug exposures occurred when VIREAD was administered to patients with moderate to severe renal
impairment [See Clinical Pharmacology (12.3). Therefore, the dosing interval of VIREAD should be adjusted in patients with
baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are
based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects with varying degrees of renal
impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval
adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment,
therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and
Precautions (5.3)].

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50-80 mL/min). Routine
monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal
impairment [See Warnings and Precautions (5.3)].

1 e l baT . Dosage Adjustment for Patients with Altered Creatinine Clearance

Creatinine Clearance
(mL/min)a
Hemodialysis Patients
>50 30-49 10-29
Recommended 300 Every 24 Every 48 Every 72
Every 7 days or after a total of
mg Dosing Interval hours hours to 96
hours approximately 12 hours of dialysisb
 a. Calculated using ideal (lean) body weight.
b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VlREAD should be
administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10
mL/min; therefore, no dosing recommendation is available for these patients.

3. DOSAGE FORMS AND STRENGTHS

VlREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of
tenofovir disoproxil. The tablets are almond-shaped, white, film-coated, and debossed with "GILEAD" and "4331" on one side.

4. CONTRAINDICATIONS
Hypersensitivity to tenofovir, tenofovir disoproxil fumarate or to any of the excipients.

5. WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside
analogs, including VlREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity
a n d prolonged nucleoside exposure may be risk factors. Particular caution should b e exercised when administering
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 VlREAD should be suspended in any patient who develops clinical or laboratory
findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in
the absence of marked transaminase elevations).
2 . 5 Exacerbation of Hepatitis after Discontinuation of Treatment
Severe acute exacerbations of hepatitis have been reported in patients coinfected with HBV and HIV-1 and have discontinued
VIREAD. Patients who are coinfected with HIV-1 and HBV who discontinue VIREAD should be closely monitored with both
clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis
B therapy may be warranted.

3 . 5 New Onset or Worsening Renal Impairment

Tenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi
syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse
Reactions (6.2)].

It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate
during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be
performed in patients at risk for renal impairment.
Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine
clearance <50 mL/min [See Dosage and Administration (2.2)]. No safety or efficacy data are available in patients with renal
impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be
assessed against the potential risk of renal toxicity.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.

5.4 Coadministration with Other Products

VIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir
disoproxil fumarate is a component of these products.

VIREAD should not be administered in combination with HEPSERA® (adefovir dipivoxil) [See Drug Interactions (7.4)].

5.5 Patients Coinfected with HIV-1 and HBV

It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with
VIREAD.

5.6 Decreases in Bone Mineral Density

Bone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or are
at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such
supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should
 be obtained.
In HIV-infected patients treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at
the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease
from baseline in BMD at the lumbar spine in patients receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with
patients receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two
treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the
reduction in BMD occurred in the first 24-48 weeks of the study and this reduction was sustained through Week 144. Twenty-
eight percent of VIREAD-treated patients vs. 21% of the stavudine-treated patients lost at least 5% of BMD at the spine or 7%
of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 patients in the VIREAD group
and 6 patients in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism
(serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the
VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and
1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes
resulted in values that remained within the normal range. The effects of VIREAD-associated changes in BMD and biochemical
markers on long-term bone health and future fracture risk are unknown.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported
in association with the use of VIREAD [See Adverse Reactions (6.2)].

7 . 5 Fat Redistribution
In HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo
hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients
receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently
unknown. A causal relationship has not been established.

8 . 5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy,
including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds
may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection,
cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and
treatment.
5.9 Early Virologic Failure
Clinical studies in HIV-infected patients have demonstrated that certain regimens that only contain three nucleoside reverse
transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with
either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and
high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution.
Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment
modification.

6. ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].

• Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].

• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].
• Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].

• Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].

6.1 Adverse Reactions from Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in
practice.
Clinical Trials in Patients with HIV Infection
More than 12,000 patients have been treated with VIREAD alone or in combination with other antiretroviral medicinal products
for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 patients have received
VIREAD 300 mg once daily in clinical trials; over 11,000 patients have received VIREAD in expanded access studies.
The most common adverse reactions (incidence ≥10%, Grades 2-4) identified from any of the 3 large controlled clinical trials
include rash, diarrhea, headache, pain, depression, asthenia, and nausea.

Treatment-Naïve Patients
Study 903 - Treatment-Emergent Adverse-Reactions: The most common adverse reactions seen in a double-blind
comparative controlled study in which 600 treatment-naïve patients received VIREAD (N=299) or stavudine (N=301) in
combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and
dizziness.

Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and
nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.

Table 2. Selected Treatment-Emergent Adverse Reactionsa (Grades 2-4) Reported in >5% in

Any Treatment Group in Study 903 (0-144 Weeks)

VIREAD + 3TC + EFV d4T + 3TC + EFV

N=299 N=301
Body as a Whole
Headache 14% 17%
Pain 13% 12%
Fever 8% 7%
Abdominal pain 7% 12%
Back pain 9% 8%
Asthenia 6% 7%
Digestive System
Diarrhea 11% 13%
Nausea 8% 9%
Dyspepsia 4% 5%
Vomiting 5% 9%
Metabolic Disorders
Lipodystrophyb 1% 8%
Musculoskeletal
Arthralgia 5% 7%
Myalgia 3% 5%
Nervous System
Depression 11% 10%
Insomnia 5% 8%
Dizziness 3% 6%
Peripheral neuropathyc 1% 5%
Anxiety 6% 6%
Respiratory
Pneumonia 5% 5%
Skin and Appendages
Rash eventd 18% 12%

a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.
b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.
c. Peripheral neuropathy includes peripheral neuritis and neuropathy.
d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.

Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common
in the stavudine group (40% and 9%) compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observed
in this study occurred with similar frequency in the VIREAD and stavudine treatment arms. A summary of Grade 3 and 4
laboratory abnormalities is provided inTable 3.

Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD Patients in Study 903 (0-144 Weeks)
VIREAD + 3TC + EFV d4T + 3TC + EFV
N=299 N=301
Any ≥ Grade 3 Laboratory 36% 42%
Abnormality

Fasting Cholesterol 19% 40%

(>240 mg/dL)

Creatine Kinase 12% 12%

(M: >990 U/L)
(F: >845 U/L)
Serum Amylase (>175 U/L) 9% 8%

AST 5% 7%
(M: >180 U/L)
<F: >170 U/L)

ALT 4% 5%
(M: >215 U/L)
(F: >170 U/L)
Hematuria (>100 RBC/HPF) 7% 7%
Neutrophils (<750/mm3) 3% 1%
Fasting Triglycerides (>750 1% 9%
mg/dL)

Treatment-Experienced Patients
Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment experienced patients were generally
consistent with those seen in treatment naïv e patients including mild to moderate gastrointestinal events, such as nausea,
diarrhea, vomiting, and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to
gastrointestinal adverse reactions (Study 907).
A summary of moderate to severe, treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907
is provided in Table 6.

Table 6 Selected Treatment-Emergent Adverse Reactionsa (Grades 2-4) Reported in

>3% in Any Treatment Group in Study 907 (0-48 Weeks)
Placebo Crossover
VIREAD Placebo VIREAD to
(N=368) (N=182) (N=368) VIREAD
(Week 0-24) (Week 0-24) (Week 0-48) (N=170)
(Week 24-48)
Body as a Whole
Asthenia 7% 6% 11% 1%
Pain 7% 7% 12% 4%
Headache 5% 5% 8% 2%

Abdominal pain 4% 3% 7% 6%
Back pain 3% 3% 4% 2%
Chest pain 3% 1% 3% 2%
Fever 2% 2% 4% 2%
Digestive System
Diarrhea 11% 10% 16% 11%
Nausea 8% 5% 11% 7%
 Vomiting 4% 1% 7% 5%
Anorexia 3% 2% 4% 1%
Dyspepsia 3% 2% 4% 2%
Flatulence 3% 1% 4% 1%
Respiratory
Pneumonia 2% 0% 3% 2%
Nervous System
Depression 4% 3% 8% 4%
Insomnia 3% 2% 4% 4%
Peripheral 3% 3% 5% 2%
neuropathyb
Dizziness 1% 3% 3% 1%
Skin and Appendage
Rash eventc 5% 4% 7% 1%
Sweating 3% 2% 3% 1%
Musculoskeletal
Myalgia 3% 3% 4% 1%
Metabolic
Weight loss 2% 1% 4% 2%

Laboratory Abnormalities: Laboratory abnormalities observed in this study occured with similar frequency in the VIREAD
and placebo-treated groups. A summary Grade 3 and 4 laboratory abnormalities is provided in Table 7.

Table 7. Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-treated Patients In Study 907 (0-48 Weeks)

Placebo
VIREAD Placebo VIREAD Crossover to
(N=368) (N=182) (N=368) VIREAD
(Week 0-24) (Week 0-24) (Week 0-48) (N=170)
(Week 24-48)
A n y ≥ Grade 3 25% 38% 35% 34%
Laboratory
Abnormality

Triglycerides (>750 mg/dL) 8% 13% 11% 9%

Creatine 7% 14% 12% 12%
Kinase (M:
>990U/L)
(F: >845 U/L)
Serum Amylase (>175 U/L) 6% 7% 7% 6%
Glycosuria (>3+) 3% 3% 3% 2%
AST 3% 3% 4% 5%
(M:>180U/L)
(F: >170 U/L)

ALT 2% 2% 4% 5%
(M: >215 U/L)
(F: >170 U/L)

Serum Glucose (>250 U/L) 2% 4% 3% 3%

Neutrophils (<750/mm3) 1% 1% 2% 1%
a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship
to study drug.
b. Peripheral neuropathy includes peripheral neuritis and neuropathy.
c. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of VIREAD. Because postmarketing reactions
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Immune System Disorders
allergic reaction

Metabolism and Nutrition Disorders

lactic acidosis, hypokalemia, hypophosphatemia

Respiratory, Thoracic, and Mediastinal Disorders

dyspnea

Gastrointestinal Disorders
pancreatitis, increased amylase, abdominal pain

Hepatobiliary Disorders
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma) TG

Skin and Subcutaneous Tissue Disorders

rash

Musculoskeletal and Connective Tissue Disorders

rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to
fractures), muscular weakness, myopathy

Renal and Urinary Disorders

acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis
(including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria

General Disorders and Administration Site Conditions

asthenia

The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal
tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

7. DRUG INTERACTIONS

This section describes clinically relevant drug interactions with VIREAD. Drug interactions studies are described elsewhere in
the labeling [See Clinical Pharmacology (12.3)].

7.1 Didanosine
Coadministration of VIREAD and didanosine should be undertaken with caution a n d patients receiving this combination
should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who
develop didanosine-associated adverse reactions.

When administered with VIREAD, C m a x and AUC of didanosine (administered as either the buffered or enteric-coated
formulation) increased significantly [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher
didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy.
Suppression of CD4+ cell counts has been observed in patients receiving tenofovir disoproxil fumarate (tenofovir DF) with
didanosine 400 mg daily. .
In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with VIREAD. Data
are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When coadministered, VIREAD
a n d didanosine EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat). Coadministration of
didanosine buffered tablet formulation with VIREAD should be under fasted conditions.
7.2 Atazanavir
Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this
interaction is unknown. Patients receiving atazanavir and VIREAD should be monitored for VIREAD-associated adverse
reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.
VIREAD decreases the AUC and C min of atazanavir [See Clinical Pharmacology (12.3)].
When coadministered with VIREAD, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir
without ritonavir should not be coadministered with VIREAD.
7.3 Lopinavir/Ritonavir
Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism
of this interaction is unknown. Patients receiving lopinavir/ritonavir and VIREAD should be monitored for VIREAD-associated
adverse reactions. VIREAD should be discontinued in patients who develop VIREAD-associated adverse reactions.
7.4 Drugs Affecting Renal Function

Since tenofovir is primarily eliminated by the kidneys [See Clinical Pharmacology (12.3)], coadministration of VIREAD with
drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or
increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir,
acyclovir, valacyclovir, ganciclovir, and valganciclovir. Drugs that decrease renal function may also increase serum
concentrations of tenofovir.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body
surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are,
however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, VIREAD should be used during pregnancy only if clearly 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 011-910-256-
0238 (call collect) or contact the registry by Fax: 011-910-256-0637 or on the worldwide web at www.kendle.com/registries/.

8.3 Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-Infected mothers not breast-
feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is
secreted in milk. It is not known whether tenofovir is excreted in human milk. Because of both the potential for HIV-1
transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-
feed if they are receiving VIREAD.

8.4 Pediatric Use

Safety and effectiveness in patients less than 18 years of age have not been established.

8.5 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
g re a te r frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.

8.6 Patients with Impaired Renal Function

It is recommended that the dosing interval for VIREAD be modified in patients with creatinine clearance <50 mL/min or in
patients with ESRD who require dialysis [See Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

9 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed
that dizziness has been reported during treatment with tenofovir disoproxil fumarate.
 01 OVERDOSAGE
Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In Study 901, 600
mg tenofovir disoproxil fumarate 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.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300
mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

1 1 DESCRIPTION
VIREAD is the brand name for tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric acid salt of bis-
isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an
acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1
reverse transcriptase.

The chemical name of tenovir disoproxil fumarate is 9-[(R)-2-

[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of
C 19H 30N 5O10P.C 4H 4O4 and a molecular weight of 635.32. It has the following structural formula:

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25
°C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.

VIREAD tablets are for oral administration. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to
245 mg of tenofovir disoproxil, and the following inactive ingredients: croscarmellose sodium, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II 32K18425,
which contains hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin.
In this insert, all dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [See Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics
The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthyvolunteers and HIV-1 infected
individuals. Tenofovir pharmacokinetics are similar between these populations.
Absorption
VIREAD is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from VIREAD
in fasted patients is approximately 25%. Following oral administration of a single dose of VIREAD 300 mg to HIV-1 infected
patients in the fasted state, maximum serum concentrations (C max ) are achieved in 1.0 ± 0.4 hrs. C max and AUC values are
0.30 ± 0.09 µg/mL and 2.29 ± 0.69 µg.hr/mL, respectively.
The pharmacokinetics of tenofovir are dose proportional over a VIREAD dose range of 75 to 600 mg and are not affected by
repeated dosing.
Distribution
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir
concentration range 0.01 to 25 µg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, follow ing
intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates
. semyzneofPYC

Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir
within 72 hours of dosing. Following single dose, oral administration of VIREAD, the terminal elimination half-life of tenofovir is
approximately 17 hours. After multiple oral doses of VIREAD 300 mg once daily (under fed conditions), 32 ± 10% of the
administered dose is recovered in urine over 24 hours.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for
elimination with other compounds that are also renally eliminated.
Effects of Food on Oral Absorption
Administration of VIREAD following a high-fat meal (~7 0 0 to 1000 kcal containing 40 to 50% fat) increases the oral
bioavailability, with an increase in tenofovir AUC 0-∞ o f approximately 40% and an increase in C max of approximately 14%.
However, administration of VIREAD with a light meal did not have a significant effect on the pharmacokinetics of tenofovir
when compared
C r i vto
o ffasted
one t oadministration
t emi t eh t ofsythe
a l edrug.
d dooF . r uoh 1 y l e t ami xo r ppa
x amyb f o CUAxCadmna
tenofovir are 0.33 ± 0.12 µg/mL and 3.32 ± 1.37 µg.hr/mL following multiple doses of VIREAD 300 mg once daily in the fed
state, when meal content was not controlled.
Special Populations
Race: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential
pharmacokinetic differences among these populations.
Gender: Tenofovir pharmacokinetics are similar in male and female patients.
Pediatric and Geriatric Patients: Pharmacokinetic studies have not been performed in children (<18 years) or in the elderly
(>65 years).
Patients with Impaired Renal Function: The pharmacokinetics of tenofovir are altered in patients with renal impairment [See
Warnings and Precautions (5.3)]. In patients with creatinine clearance <50 mL/min or with end-stage renal disease (ESRD)
requiring dialysis, C max , and AUC 0-∞ of tenofovir were increased (Table 8). It is recommended that the dosing interval for
VIREAD be modified in patients with creatinine clearance <50 mL/min or in patients with ESRD who require dialysis [See
Dosage and Administration (2.2)].

Table 8 Pharmacokinetic Parameters (Mean ± SD) of Tenofovira in Patients with Varying Degrees of Renal Function
Baseline Creatinine >80 50-80 30-49 12-29
Clearence (mL/min) (N=3) (N=10) (N=8) (N=11)
C max (µg/mL) 0.34±0.03 0.33±0.06 0.37±0.16 0.60±0.19
AUC 0-∞ (µg.hr/mL) 2.18±0.26 3.06±0.93 6.01±2.50 15.98±7.22
CL/F (mL/min) 1043.7±115.4 807.7±279.2 444.4±209.8 177.0±97.1
CLrenal (mL/min) 243.5±33.3 168.6±27.5 100.6±27.5 43.0±31.2
a. 300 mg, single dose of
VIREAD

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300
mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg single dose of VIREAD have been
studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in
tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. No change in VIREAD
dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism
mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but
statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments
and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving tenofovir with other
medicinal products is low [See Clinical Pharmacology (12.3)].
VIREAD has been evaluated in healthy volunteers in combination with abacavir, atazanavir, didanosine, efavirenz,
emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin,
saquinavir/ritonavir, and tacrolimus. Tables 9 and 10 summarize pharmacokinetic effects of coadministered drug on tenofovir
pharmacokinetics and effects of VIREAD on the pharmacokinetics of coadministered drug.
Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in th e Presence of the
Coadministered Drug

a. Patients received VIREAD 300 mg once daily.

b. Increase = ↑; Decrease = ↓; No Effect = Û; NC = Not Calculated

c. Reyataz Prescribing Information

Following multiple dosing to HIV- and HBV-negative subjects receiving either chronic methadone maintenance therapy or oral
contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous
studies, indicating lack of clinically significant drug interactions between these agents and VIREAD.

Table.10 Drug Interaction: Change In Pharmacokinetic Parameters for Coadministration in the Precence of Viread
 a. Increase = ↑; Decrease = ↓: No Effect = Û; NA = Not Applicable
b. Reyataz Prescribing Information
c. In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg. resulted in AUC and Cmin values of atazanavir that
were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
. h) et vi w
i t cr aod. ( e- R
n o l a d e s o d n e hw t n e l a v i u q e
e. Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or
symptoms) were reported.
t ls o
e b al t yenm i f.e
h vt Ei t c a y l l a c i g o l o c am r a h p ( when dosed alone or with VIREAD.
g. Increases in AUC and Cmin are not expected to be clinically relevant: hence no dose adjustments are required when tenofovir DF and
ritonavir-boosted saquinavir are coadministered.

Table 11 summarizes the drug interaction between VIREAD and didanosine. Coadministration of VIREAD and didanosine
should be undertaken with caution [See Drug Interactions (7.1)]. When administered with multiple doses of VIREAD, the C max
and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250
mg enteric-coated capsules were administered with VIREAD, systemic exposures to didanosine were similar to those seen
with the 400 mg enteric-coated capsules alone under fasted conditions.

Table 11 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD
 . a Administration with food was with a light meal (~373 kcal. 20% fat).
. b Increase = ↑; Decrease = ↓: No Effect = Û
. c Includes 4 subjects weighing <60 kg receiving ddl 250 mg.

12.4 Microbiology
Mechanism of Action
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir
disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular
enzymes to form tenofovir diphosphate, an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1
reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into
DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and
mitochondrial DNA polymerase γ.
Activity against HIV
Antiviral Activity
The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines,
primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC 50 (50% effective concentration) values for
tenofovir were in the range of 0.04 µM to 8.5 µM. In drug combination studies of tenofovir with nucleoside reverse transcriptase
inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase
inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir),
additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C,
D, E, F, G, and O (EC 50 values ranged from 0.5 µM to 2.2 µM) and strain specific activity against HIV-2 (EC 50 values ranged
from 1.6 µM to 5.5 µM).

na t s i seR
HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R
substitution in reverse transcriptase and showed a 2-4 fold reduction in susceptibility to tenofovir.
In Study 903 of treatment-naïve patients (VIREAD + lamivudine + efavirenz versus stavudine + lamivudine + efavirenz) [See
Clinical Studies (14.1)], genotypic analyses of isolates from patients with virologic failure through Week 144 showed
development of efavirenz and lamivudine resistance-associated substitutions to occur most frequently and with no difference
between the treatment arms. The K65R substitution occurred in 8/47 (17%) analyzed patient isolates on the VIREAD arm and
in 2/49 (4%) analyzed patient isolates on the stavudine arm. Of the 8 patients whose virus developed K65R in the VIREAD arm
through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and one at Week 96. Other substitutions resulting in
resistance to VIREAD were not identified in this study.
 Cross Resistance
Cross-resistance among certain reverse transcriptase inhibitors has been recognized. The K65R substitution selected by
tenofovir is also selected in some HIV-1 infected subjects treated with abacavir, didanosine, or zalcitabine. HIV-1 isolates with
this mutation also show reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these drugs
may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed
a mean of 3 zidovudine-associated reverse transcriptase substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N),
showed a 3.1-fold decrease in the susceptibility to tenofovir. Multinucleoside resistant HIV-1 with a T69S double insertion
substitution in the reverse transcriptase showed reduced susceptibility to tenofovir.
In Studies 902 and 907 conducted in treatment-experienced patients (VIREAD+) . Standard Background Therapy (SBT)
compared to Placebo + SBT) [See Clinical Studies (14.1)], 14/304 (5%) of the VIREAD-treated patients with virologic failure
through Week 96 had > 1.4-fold (median 2.7-fold) reduced susceptibility to tenofovir. Genotypic analysis of the baseline and
failure isolates showed the development of the K65R substitution in the HIV-1 reverse transcriptase gene.

The virologic response to VIREAD therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment-
experienced patients participating in Studies 902 and 907.
In these clinical studies, 94% of the participants evaluated had baseline HIV-1 isolates expressing at least one NRTI mutation.
These included resistance substitutions associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N),
th e abacavir/emtricitabine/lamivudine resistance-associated substitution (M184V), and others. In addition the majority of
participants evaluated had substitutions associated with either PI or NNRTI use. Virologic responses for patients in the
genotype substudy were similar to the overall study results.
Several exploratory analyses were conducted to evaluate the effect of specific substitutions and substitutional patterns on
virologic outcome. Because of the large number of potential comparisons, statistical testing was not conducted. Varying
degrees of cross-resistance of VIREAD to pre-existing zidovudine resistance-associated substitutions were observed and
appeared to depend on the number of specific substitutions. VIREAD-treated patients whose HIV-1 expressed 3 or more
zidovudine resistance-associated substitutions that included either the M41L or L210W reverse transcriptase substitution
showed reduced responses to VIREAD therapy; however, these responses were still improved compared with placebo. The
presence of the D67N, K70R, T215Y/F, or K219Q/E/N substitution did not appear to affect responses to VIREAD therapy.
In the protocol defined analyses, virologic response to VIREAD was not reduced in patients with HIV-1 that expressed the
abacavir/emtricltabine/lamivudine resistance-associated M184V substitution. In the presence of zidovudine resistance-
associated substitutions, the M184V substitution did not affect the mean HIV-1 RNA responses to VIREAD treatment. HIV-1
RNA responses among these patients were durable through Week 48.
Studies 902 and 907 Phenotypic Anlayses
The virologic response to VIREAD therapy has been evaluated with respect to baseline phenotype (N=100) in treatment-
experienced patients participating in two controlled trials. Phenotypic analysis of baseline HIV-1 from patients in these studies
demonstrated a correlation between baseline susceptibility to VIREAD and response to VIREAD therapy. Table 12
summarizes the HIV-1 RNA response by baseline VIREAD susceptibility.

21 e l baT - t ne t n) It a( e rT - oT a

Baseline VIREAD Susceptibilityb Change in HIV-1 RNA c (N)

<1 -0.74 (35)
>1 and ≤ 3 -0.56 (49)
> 3 and ≤ 4 -0.3 (7)
>4 -0.12 (9)

a. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram assay (Virco).

b. Fold change in susceptibility from wild-type.
c. Average HIV-1 RNA change from baseline through Week 24 (DAVG24) in log10 copies/ml.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to
 approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the
high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was
negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial
mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when
administered
. ec im etol am
There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was
administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28
days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an
alteration of the estrous cycle in female rats.
13.2 Animal Toxicology and/or Pharmacology
Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based
on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was
diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or
discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s)
underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria,
phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These
toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the
renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14 CLINICAL STUDIES
14.1 Treatment-Naïve Patients
Study 903

Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD
(300 mg once daily) administered in combination with lamivudine and efavirenz versus stavudine (d4T), lamivudine, and
efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18-64), 74% were male, 64% were
Caucasian and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3-956) and median baseline
plasma HIV-1 RNA was 77,600 copies/mL (range 417-5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4+
cell count. Forty-three percent patients had baseline viral loads >100,000 copies/mL and 39% had CD4+ cell counts <200
cells/mm3. Treatment outcomes through 48 and 144 weeks are presented in Table 13.

31 e l baT

At Week 48 At Week 144

CT3+DAER I V d4T+3TC CT3+DAER I V d4T+3TC
Outcomes +EFV +EFV +EFV +EFV
(N=299) (N=301) (N=299) (N=301)
Respondera 79% 82% 68% 62%

Virologic failureb 6% 4% 10% 8%

Rebound 5% 3% 8% 7%
Never suppressed 0% 1% 0% 0%
Added an 1% 1% 2% 1%
antiretroviral
agent
Death <1% 1% <1% 2%
Discontinued due to 6% 6% 8% 13%
adverse event
Discontinued for 8% 7% 14% 15%
other reasonsc
hc a s t n e a.
i t aP hguo r h t Lm / s e i p o c A N0R.0 4 4
<1 dna 84 k e eW
f noc s e d u b.
l cn I . 441 dna 84 k e eW h g u o r h t
t so l s e dc.
u l cIn . s nos ae r r eh t o dna no i t a l o i v

Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at Week 144 was similar between the two
treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤ 100,000 copies/mL)
and CD4+ cell count (< or ≥200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of patients in the VIREAD and
stavudine arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/mL. The mean increase from
baseline in CD4+ cell count was 263 cells/mm3 for the VIREAD arm and 283 cells/mm3 for the stavudine arm.

Through 144 weeks, 11 patients in the VIREAD group and 9 patients in the stavudine group experienced a new CDC Class
C event.

14.2 Treatment-Experienced Patients

Study 907
Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background
regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients
continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients had a mean baseline CD4+ cell
count of 427 cells/mm3 (range 23-1385), median baseline plasma HIV-1 RNA of 2340 (range 50-75,000) copies/mL, and mean
duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were
Caucasian, 17% Black and 12% Hispanic.
Changes from baseline in log10 copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure
1.

The percent of patients with HIV-1 RNA <400 copies/mL and outcomes of patients throught 48 weeks are summarized in Table
15.

Table 15 Outcomes of Randomized Treatment (Study 907)

0-24 weeks 0-48 weeks 24-48 weeks
Outcomes VIREAD Placebo VIREAD Placebo
(N=368) (N=182) (N=368) Crossovers
toVIREAD
(N=170)
HIV-1 RNA 40% 11% 28% 30%
<400
copies/mLa
Virologic failureb 53% 84% 61% 64%

Discontinued 3% 3% 5% 5%
due to adverse
event

Discontinued for 3% 3% 5% 1%
other reasonsc

a. Patients with HIV-1 RNA <400 copies/mL and no prior study drug discontinuation at Week 24 and 48 respectively. '
b. Patients with HIV-1 RNA ≥400 copies/ml efficacy failure or missing HIV-1 RNA at Week 24 and 48 respectively.
c. Includes lost to follow-up, patient withdrawal, noncompliance, protocol violation and other reasons.

At 24 weeks of therapy, there was a higher proportion of patients in the VIREAD arm compared to the placebo arm with HIV-1 RNA
<50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4+ cell counts by Week 24 was +11 cells/mm3 for the
VIREAD group and -5 cells/mm3 for the placebo group. Mean change in absolute CD4+ cell counts by Week 48 was +4 cells/mm
for the VIREAD group.

Through Week 24, one patient in the VIREAD group and no patients in the placebo arm experienced a new CDC Class C event.

16 HOW SUPPLIED/STORAGE AND HANDLING

VIREAD is an almond-shaped, white, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to
245 mg of tenofovir disoproxil, are debossed with "GILEAD" and "4331" on one side, and are available in unit of use bottle
(containing a desiccant [silica gel canister or sachet] and closed with a child-resistant closure) of:
· 30 tablets per bottle

· Net weight (tablet weight): 667 mg

· Store below 30 °C (86 °F).

· Keep container tightly closed.
· Dispense only in original container.
· Do not use if seal over bottle opening is broken or missing.

HARUS DENGAN RESEP DOKTER

License No. DKI1192100210A1

Distributed by. PT IDS Marketing Indonesia

Manufactured for (applicant):

Gilead Sciences, Inc., Foster City, CA 94404 USA

Manufactured bv:
Nycomed GmbH, 16515 Oranienburg. Germany

November 2008
TRUVADA, EMTRIVA, HEPSERA and VIREAD are registered trademarks of Gilead Sciences, Inc. ATRIPLA is a trademark of
Bristol-Myers Squibb & Gilead Sciences, LLC. All other trademarks referenced herein are the property of their respective
owners.
TVD-022A-IDN-ENG-YYYY-MMM