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Changes to Complera (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) labeling

On December 13, 2013, FDA approved changes to the Complera (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) label to include the use of Complera for the treatment of HIV-1 infection in certain adult patients who are virologically suppressed on a stable ritonavir-boosted protease inhibitor regimen. Specifically the following changes were made.

 
INDICATIONS AND USAGE
 
COMPLERA, a combination of two nucleoside analog HIV 1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV 1 infection in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen.
 
The efficacy of COMPLERA was established in patients who were virologically-suppressed (HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor-containing regimen. The following points should be met when considering replacing the current regimen with COMPLERA in virologically-suppressed adults [See Clinical Studies (14)]:
  • Patients should have no history of virologic failure.
  • Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to switching therapy.
  • Patients should currently be on their first or second antiretroviral regimen prior to switching therapy.
  • Patients should have no current or past history of resistance to any of the three components of COMPLERA.
Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.
 
ADVERSE REACTIONS
 
In Virologically-Suppressed HIV-1-Infected Subjects
No new adverse reactions to COMPLERA were identified in stable, virologically-suppressed subjects switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA.
 
Microbiology
 
In Virologically-Suppressed HIV-1-Infected Subjects
 
Study 106: Through Week 48, four subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and one subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug.  All four of the subjects who had resistance emergence on COMPLERA had evidence of emtricitabine resistance and three of the subjects had evidence of rilpivirine resistance.
 
CLINICAL STUDIES
 
In Virologically-Suppressed HIV-1-Infected subjects
 
The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination with two NRTIs to COMPLERA was evaluated in Study 106, a randomized, open-label study in virologically-suppressed HIV-1-infected adults.  Subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of COMPLERA, and must have been suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to screening.  Subjects were randomized in a 2:1 ratio to either switch to COMPLERA at baseline (COMPLERA arm, N = 317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, N = 159) and then switch to COMPLERA for an additional 24 weeks (N =152).  Subjects had a mean age of 42 years (range 19-73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino.  The mean baseline CD4+ cell count was 584 cells/mm3 (range 42–1484).  Randomization was stratified by use of tenofovir DF and/or lopinavir/ritonavir in the baseline regimen.
Treatment outcomes are presented in Table 10.
 
Table 10           Virologic Outcomes of Randomized Treatment in Study GS-US-264-0106 
 

 
COMPLERA
Stayed on Baseline Regimen (SBR)
Week 48a
Week 24b
N = 317
N = 159
HIV-1 RNA <50 copies/mLc 
89% (283/317)
90% (143/159)
HIV-1 RNA ≥50 copies/mLd 
3% (8/317)
5% (8/159)
No Virologic Data at Week 24 Window 
 
 
Discontinued Study Drug Due to AE or Deathe
2% (7/317)
0%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mLf
5% (16/317)
3% (5/159)
Missing Data During Window but on Study Drug
1% (3/317)
2% (3/159)

a.   Week 48 window is between Day 295 and 378 (inclusive). 
b.   For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to COMPLERA, the Week 24 window is between Day 127 and first dose day on COMPLERA. 
c.   Predicted difference (95% CI) of response rate for switching to COMPLERA at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is -0.7% (‑6.4% to 5.1%).
d.   Includes subjects who had HIV-1 RNA ≥50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had a viral load value of ≥50 copies/mL.
e.   Includes subjects 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.
f.    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.
 
You can view the entire revised label at Drugs@FDA.
 
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