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Complera Labeling Update: No Longer Recommended at High Viral Loads; Hepatotoxicity Precaution Added

January 28, 2013

On January 25, 2013, FDA approved changes to the Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) package insert. The major changes include restricting the indication to treatment-naive adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL, updating the package insert with the 96-week results from the Phase 3 trials and adding a new Contraindication and new Warning and Precaution for hepatotoxicity. Below is a summary of the recent changes.


Section 1: Indications and Usage

Complera, a combination of 2 nucleoside analog HIV‑1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and 1 non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV‑1 infection in treatment-naive adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL.

This indication is based on safety and efficacy analyses through 96 weeks from 2 randomized, double‑blind, active controlled, Phase 3 trials in treatment‑naive subjects.

The following points should be considered when initiating therapy with COMPLERA:


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Section 4: Contraindications

Dexlansoprazole was added to the list of Contraindicated medications.


Section 5.6: Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C, or marked elevations in serum liver biochemistries prior to treatment may be at increased risk for worsening or development of serum liver biochemistries elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in serum liver biochemistries prior to treatment initiation. Serum liver biochemistries monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.


Section 6: Adverse Reactions

Updated with the Week 96 data from the phase 3 trials TMC278-C209 and TMC278-C215. Nephrolithiasis was added to the Less common adverse drug reactions subsection.


Section 6.2: Postmarketing Experience

Nephrotic syndrome was added to the postmarketing experience subsection.


Section 7: Drug Interactions

Troleandomycin was removed from the table 7. Telithromycin was added with the clinical comment that telithromycin may cause an increase increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.


Section 12.4: Microbiology

Updated with the Week 96 data. The following new paragraph was also added to this section.

NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of ≤100,000 copies/mL compared to viruses from subjects with baseline viral loads of >100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts <200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.


Section 14: Clinical Studies

Updated as follows:

The virologic outcome of randomized treatment of studies TMC278-C209 and TMC278-C215 at Week 96 is represented in the following table:


 Rilpivirine
+ FTC/TDF
N=550
Efavirenz
+ FTC/TDF
N=546

HIV-1 RNA <50 copies/mLb

77%

77%

HIV-1 RNA ≥50 copies/mLc

14%

8%

No virologic data at Week 96 window

Reasons

Discontinued study due to adverse event or deathd

4%

9%

Discontinued study for other reasonse and the last available HIV-1 RNA <50 copies/mL (or missing)

4%

6%

Missing data during window but on study

<1%

<1%

HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL)

≤100,000

83%

80%

>100,000

71%

74%

HIV-1 RNA ≥50 copies/mLc by Baseline HIV-1 RNA (copies/mL)

≤100,000

7%

5%

>100,000

22%

12%

HIV-1 RNA <50 copies/mL by Baseline CD4+ Cell Count (cells/mm3)

<200

68%

72%

≥200

82%

79%

HIV-1 RNA ≥50 copies/mLc by Baseline CD4+ Cell Count (cells/mm3)

<200

27%

12%

≥200

8%

7%

  1. Analyses were based on the last observed viral load data within the Week 96 window (Week 90-103).
  2. Predicted difference (95% CI) of response rate is 0.5% (-4.5% to 5.5%) at Week 96.
  3. Includes subjects who had ≥50 copies/mL in the Week 96 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, and subjects who had a switch in background regimen that was not permitted by the protocol.
  4. Includes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window.
  5. 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.


The complete updated label will become available shortly on FDA's website at Drugs@FDA.




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