HIV/AIDS Update - Labeling updates for Edurant (rilpivirine)

On December 7, 2012, FDA approved changes to the Edurant (rilpivirine) package insert. The major changes include restricting the indication to treatment-naïve 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 Warning and Precaution for hepatotoxicity. Below is a summary of the recent changes.
INDICATIONS AND USAGE
EDURANT, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in antiretroviral treatment‑naïve adult patients with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.
This indication is based on safety and efficacy analyses through 96 weeks from 2 randomized, double‑blind, active controlled, Phase 3 trials in treatment‑naïve subjects [see Clinical Studies (14.1)].
The following points should be considered when initiating therapy with EDURANT:

• More EDURANT treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥ 50 copies/mL) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL
• Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm³ experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm³
• The observed virologic failure rate in EDURANT treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
• More subjects treated with EDURANT developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz

5.3 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 transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of EDURANT. 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 EDURANT is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.
Section 6 Adverse Reactions was 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.
Nephrotic syndrome was added to the postmarketing experience subsection.
In 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 was updated with the Week 96 data. The following new paragraph was added to this section.
NNRTI- and NRTI-resistance substitutions emerged less frequently in resistance analysis of viruses from subjects with baseline viral load of ≤ 100,000 copies/mL compared to viruses from subjects with baseline viral load of > 100,000 copies/mL: 26% (14/54) compared to 74% (40/54) of NNRTI-resistance substitutions and 22% (11/50) compared to 78% (39/50) of NRTI-resistance substitutions. This difference was also observed for the individual emtricitabine/lamivudine and tenofovir resistance substitutions: 23% (11/47) compared to 77% (36/47) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline CD4+ cell counts ≥ 200 cells/mm³ compared to viruses from subjects with baseline CD4+ cell counts < 200 cells/mm³: 37% (20/54) compared to 63% (34/54) of NNRTI-resistance substitutions and 28% (14/50) compared to 72% (36/50) of NRTI-resistance substitutions.
Section 14 Clinical Studies was 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:

Table 10: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96
	EDURANT + BR** N=686	Efavirenz + BR** N=682
HIV-1 RNA < 50 copies/mL*	8376%	8077%
Virologic failureHIV-1 RNA ≥ 50 copies/mL†	1316%	910%
No virologic data at Week 96 window Reasons
Discontinued study due to adverse event or death‡	24%	78%
Discontinued study for other reasons and last available HIV-1 RNA < 50 copies/mL (or missing)§	24%	35%
Missing data during window but on study	< 1%	< 1%
HIV-1 RNA < 50 copies/mL by Baseline HIV-1 RNA (copies/mL)
≤ 100,000	8982%	8378%
> 100,000	7870%	7875%
Virologic failureHIV-1 RNA ≥ 50 copies/mL† by Baseline HIV-1 RNA (copies/mL)
≤ 100,000	59%	58%
> 100,000	2024%	11%
> 500,000HIV-1 RNA < 50 copies/mL by CD4+ cell count (cells/mm3)	29%	17%
< 200	68%	74%
≥ 200	81%	77%
HIV-1 RNA ≥ 50 copies/mL† by CD4+ cell count (cells/mm3)
< 200	27%	10%
≥ 200	10%	9%
N = total number of subjects per treatment group; BR = background regimen. * CI = Predicted difference (95% CI) of response rate is ‑0.2 (‑4.7; 4.3) at Week 96. † 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. ‡ 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.  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. 96 window (Week 90-103), respectively.

** background regimen
The complete updated label will be available soon on FDA's web site at Drugs@FDA.
Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration