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Viread (tenofovir) Labeling Revision from FDA
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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% ±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 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.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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