New Information in Viread Label
Viread labeling has been updated to include results from Gilead Sciences study 903 (antiretroviral naïve subjects). The revised label also includes new dose recommendations for patients with renal impairment, a new warning about HIV/HBV coinfection, dose recommendation for ddI when used with tenofovir, and updated information regarding bone effects.
In addition, the original label stated that Viread should be taken with a meal. New information indicates that Viread may be taken without regard to food. This information can be found in the Dosage and Administration section of the new label.
Below is a summary of the information that can be found in the updated labeling.
Description of Clinical Studies
Study 903: VIREAD + Lamivudine +Efavirenz Compared to Stavudine + Lamivudine + Efavirenz
Data through 48-weeks are reported for Study 903, a double-blind, active-controlled multicenter study comparing VIREAD (300 mg QD) administered in combination with lamivudine and efavirenz versus stavudine, lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18 to 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 count. Forty-three percent of patients had baseline viral loads > 100,000 copies/mL and 39% had CD4 cell counts <200 cells/mL. Treatment outcomes through 48 weeks are presented in Table 6 below.
Table 6. Outcomes of Randomized Treatment at Week 48 (Study 903)
|Viread + 3TC + EFV (N=299)||Stavudine +3TC +EFV (N=301)|
|Outcome at Week 48||%||%|
|Never suppressed through Week 48||0%||1%|
|Added an antiretroviral agent||1%||1%|
|Discontinued due to adverse event||6%||6%|
|Discontinued for other reasons||8%||7%|
1 Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48
2 Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48
3 Includes lost to follow-up, patient's withdrawal, noncompliance, protocol violation and other reasons
Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/mL at week 48 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 ³ 200 cells/mm3). Through 48 weeks of therapy, 76% and 79% of patients in the VIREAD and stavudine arms, respectively achieved HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4 cell count was 169 cells/mm3 for the VIREAD arm and 167 cells/mm3 for the stavudine arm.
Through 48 weeks, eight patients in the VIREAD group and six patients in the stavudine group experienced a new CDC Class C event
Safety information in Treatment-Naïve Patients
Treatment-Emergent Adverse Events: The 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 48 weeks (Study 903) were generally consistent, with the addition of dizziness, with those seen in treatment-experienced patients. Mild adverse events (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea and nausea.
Laboratory Abnormalities: With the exception of triglyceride elevations that were more common in the stavudine group (8%) compared with VIREAD (2%), laboratory abnormalities observed in this study occurred with similar frequency in the VIREAD and stavudine treatment arms.
Tenofovir is principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with creatinine clearance < 50 mL/min (see dosing information below). No safety data are available in patients with renal dysfunction who received VIREAD using these dosing guidelines.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of VIREAD. The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors.
VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Dose Adjustment for Renal Impairment:
Significantly increased drug exposures occurred when VIREAD was administered to patients with moderate to severe renal impairment. The dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance < 50 mL/min using the recommendations below. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated, therefore, clinical response to treatment and renal function should be closely monitored in these patients.
The recommended dosing for subjects with Creatinine Clearance > 50 (mL/min)3 is 300 mg every 24 hours
The recommended dosing for subjects with Creatinine Clearance 30 - 49 (mL/min)3 is 300 mg every 48 hours
The recommended dosing for subjects with Creatinine Clearance 10 - 29 (mL/min)3 is 300 mg twice a week
For hemodialysis patients the recommended dose is 300 mg every 7 days or after a total of approximately 12 hours of dialysis (Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. VIREAD 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.
Patients with HIV and Hepatitis B Virus Coinfection
It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. VIREAD is not indicated for the treatment of chronic HBV infection and the safety and efficacy of VIREAD have not been established in patients co-infected with HBV and HIV. Exacerbations of HBV have been reported in patients after the discontinuation of VIREAD. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping VIREAD treatment.
When administered with VIREAD, Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. In adults weighing >60kg, the didanosine dose should be reduced to 250mg when it is co-administered with VIREAD. Data are not available to recommend a dose adjustment of didanosine for patients weighing < 60 kg. When co-administered, VIREAD and didanosine EC may be taken under fasted conditions or with a light meal <400 kcal, =20% fat). Co-administration of didanosine buffered tablet formulation with VIREAD should be under fasted conditions. Co-administration of VIREAD and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.
In study 903 through 48 weeks, decreases from baseline in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At 48 weeks, percent decreases in BMD from baseline (mean ± SD) were greater in patients receiving VIREAD + lamivudine + efavirenz (spine, -3.3% ± 3.9 ; hip, -3.2% ± 3.6) compared with patients receiving stavudine + lamivudine + efavirenz (spine, -2.0 ± 3.5; hip. -1.8% ± 3.3). The proportion of patients who met a protocol defined value of BMD loss (5% decrease in spine or 7% decrease in hip) was higher in the VIREAD group than the stavudine group. In addition, there were significant increases in levels of four 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 were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range. There was one bone fracture reported in the VIREAD group compared with four in the stavudine group; no pathologic fractures were identified over 48 weeks of study treatment. The clinical significance of the changes in BMD and biochemical markers is unknown and follow-up is continuing to assess long-term impact.
Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at substantial risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected then appropriate consultation should be obtained.
Office of Special Health Issues
Food and Drug Administration
Division of Antiviral Drug Products
Food and Drug Administration