On May 12, 2005, FDA approved new labeling for Viread
(tenofovir disoproxil fumarate). The label was updated to include results
from Study 903, specifically, the 144 week efficacy and safety data in
treatment-naïve patients. Study 903 fulfills part of the requirement for
traditional approval by confirming long-term efficacy in treatment-naïve
patients and by providing long-term safety information with respect to bone
effects.

The following changes were made to the package insert:

Description of Clinical Studies:
The 144-week efficacy data from Study 903 was added.
Sixty-eight percent of patients who received Viread in combination with
Epivir (lamivudine) and Sustiva (efavirenz) achieved and maintained
confirmed HIV RNA < 400 copies/mL at Week 144 compared to 62% of patients
who received Zerit (stavudine) in combination with Epivir (lamivudine) and
Sustiva (efavirenz).

New text describing the genotypic analysis performed during
Study 903 was added as follows:

"Genotypic analyses of patients with virologic failure
showed development of efavirenz-associated and lamivudine-associated
mutations to occur most frequently and with no difference between the
treatment arms. The K65R mutation occurred in 8 patients on the Viread arm
and in 2 patients on the Stavudine arm. Of the 8 patients who 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 mutations resulting in
resistance to VIREAD were not identified in this study."

PRECAUTIONS:

The Bone Effects subsection was updated with Study 903 data
through 144 weeks of dosing as follows:

"In study 903 through 144 weeks, decreases from baseline in
bone mineral density (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% ±3in 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 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 8 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. 

Bone monitoring should be considered for HIV infected
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."

A new paragraph, "Immune Reconstitution Syndrome," was
added. This paragraph is being incorporated into the labels of all
antiretroviral drugs.

"Immune reconstitution syndrome has been reported in
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."
ADVERSE REACTIONS: 
* Text and tables displaying Selected Treatment-Emergent
Adverse Events (Grades 2-4) and Grade 3/4 Laboratory Abnormalities in Study
903 was updated with data through 144 weeks of dosing. 
* In the Post Marketing Experience section, increased
amylase, increased liver enzymes, hepatitis, and nephrogenic diabetes
insipidis were added to the list of reported disorders. 
Viread is a product of Gilead Science, Inc.

<<VireadLabel.pdf>> 
Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration