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On August 28, 2014, FDA approved updates to the Stribild (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir 300mg) fixed-dose combination tablets label to include:
- 144-week efficacy, resistance and safety data from two Phase 3 trials
-
- Study GS-US-236-0102 entitled, “A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults”
- Study GS-US-236-0103 entitled, “A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Emtricitabine/Tenofovir Disoproxil Fumarate/GS-9350 Versus Ritonavir-Boosted Atazanavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate in HIV-1 Infected, Antiretroviral Treatment-Naive Adults”.
- Renal information based on the 48-week efficacy, resistance, and safety data from Phase 3 Study GS-US-236-0118 entitled “A Phase 3 Open-label Safety Study of Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients with Mild to Moderate Renal Impairment”
- Drug interaction information based on Study GS-US-236-0135 entitled “A Phase 1 Multiple-Dose Study Evaluating the Drug Interaction Potential Between Telaprevir and Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Single Tablet Regimen (Part 1) or Ritonavir-Boosted Atazanavir plus Elvitegravir (Part 2) in Healthy Subjects”
The major labeling changes are summarized below.
The following updates were made to section 5.3 New Onset or Worsening Renal Impairment to reflect the 144 week data.
In the clinical trials of STRIBILD over 144 weeks, 13 (1.9%) subjects in the STRIBILD group (N=701), 8 (2.3%) subjects in the ATV + RTV + TRUVADA group (N=355) and no subjects in the ATRIPLA group (N = 352) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the ATV + RTV + TRUVADA group occurred during the first 48 weeks. Four (0.6%) subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD during the first 48 weeks of treatment. Two of the four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects. One (0.3%) subject who received ATV + RTV + TRUVADA developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of ATV + RTV + TRUVADA after Week 96.
In section 6 Adverse reactions, Tables 2-5 were updated with the 144 week data and the following information was added.
Additional adverse drug reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a pre-existing history of depression or psychiatric illness.
From study 103, the BMD and proteinuria data were updated as follows:
In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects (STRIBILD group N = 54; ATV + RTV + TRUVADA group N = 66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to the ATV + RTV + TRUVADA group at the lumbar spine (-1.43% versus -3.68%, respectively) and at the hip (-2.83% versus -3.77%, respectively). In Studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV + RTV + TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving tenofovir DF + lamivudine + efavirenz.
Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV + RTV + TRUVADA
Section 7.6: Drugs without Clinically Significant Interactions with Stribild was updated to include telaprevir. Additonally section 12 was updated with the results from the drug interaction trial.
Section 8.6 Renal Impairment was updated to include data from Study 118 as follows:
Clinical Trials in Subjects with Mild to Moderate Renal Impairment
In Study 118, 33 HIV-1 infected treatment naïve subjects with mild to moderate renal impairment (eGFR by Cockcroft-Gault method between 50 and 89 mL/minute) were studied in an open-label clinical trial evaluating the safety of 48 weeks of treatment with STRIBILD. After 48 weeks of treatment, the mean change in serum creatinine was 0.17 ± 0.14 mg/dL and the mean change in eGFR by Cockcroft-Gault method was -6.9 ± 9.0 mL/minute for subjects treated with STRIBILD.
Twelve of the 33 subjects studied had baseline eGFR between 50 and 70 mL/minute. Three subjects, all with baseline eGFR between 50-60 mL/minute, discontinued STRIBLD due to a renal adverse event. The safety of STRIBILD among 21 of the 33 subjects with baseline eGFR greater than or equal to 70 mL/minute was consistent with the safety profile in Studies 102 and 103.
Section 14 was updated with the 144 week trial results.
Table 10 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 144a
|
|
Study 102 |
Study 103 |
||
|
|
STRIBILD |
ATRIPLA |
STRIBILD |
ATV + RTV + TRUVADA |
|
Virologic Success |
8480% |
8275% |
8378% |
8275% |
|
Treatment Difference |
2.74.9% (95% CI = -1.3%, 11.1%) |
13.1% (95% CI = -3.2%, 9.4%) |
||
|
Virologic Failureb |
67% |
10% |
78% |
7% |
|
No Virologic Data at Week 96 Window |
|
|
|
|
|
Discontinued Study Drug Due to AE or Deathc |
56% |
68% |
46% |
68% |
|
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd |
5% |
47% |
58% |
59% |
|
Missing Data During Window but on Study Drug |
01% |
10% |
1% |
01% |
a. Week 144 window is between Day 967 and 1050 (inclusive).
b. Includes subjects who had ≥50 copies/mL in the Week 144 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
c. Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
d. Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.
In Study 102, the mean increase from baseline in CD4+ cell count at Week 144 was 298 cells per mm3 in the STRIBILD-treated subjects and 272 cells per mm3 in the ATRIPLA -treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 144 was 261 cells per mm3 in the STRIBILD-treated subjects and 269 cells per mm3 in the ATV + RTV + TRUVADA-treated subjects.
The complete revised label will be posted soon at DailyMed.
Stribild is a product of Gilead Sciences.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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