FDA Approved Changes to the Odefsey Label

On August 21, 2017, FDA approved changes to the Odefsey (emtricitabine/rilpivirine/tenofovir alafenamide) label to include data from 48 week data from trials in which subjects switched to Odefsey from tenofovir disoproxil fumarate based regimens (Complera (emtricitabine/rilpirivine/tenofovir disoproxil fumarate) or Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate)). The major changes to the label are summarized below.

Section 6: Adverse Reactions was updated as follows:

6.1    Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.

Adverse Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Subjects with HIV-1 Infection

The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult subjects who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively.  A total of 754 subjects received one tablet of ODEFSEY daily [see Clinical Studies (14.1)].
The most common adverse reactions (all Grades) reported in at least 2% of subjects in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1).  Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity.  The proportion of subjects who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.

Table 1  Adverse Reactions^a (All Grades) Reported in ≥1% of HIV-1 Infected Virologically-Suppressed Adults in Trial 1160 or Trial 1216 (Week 48 analysis)

Adverse Reaction	Trial 1160		Trial 1216
	ODEFSEY (N=438)	EFV/FTC/TDF(N=437)b	ODEFSEY (N=316)	FTC/RPV/TDF (N=313)b
Headache	2%	1%	0	1%
Flatulence	1%	< 1%	< 1%	1%
Sleep Disturbances	2%	1%	0	< 1%
Abnormal Dreams	1%	1%	0	2%
Diarrhea	1%	3%	1%	2%
Nausea	1%	1%	1%	1%

^a Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator.
^b Data from Trials 1160 and 1216 do not provide an adequate basis for comparison of adverse reaction incidences between ODEFSEY and the FTC/RPV/TDF and EFV/FTC/TDF groups.

Renal Laboratory Tests

In Trial 1216, the median baseline eGFR was104 mL per minute for subjects who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48.

In Trial 1160, the median baseline eGFR was 110 mL per minute for subjects who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48.

Bone Mineral Density Effects

Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160.

In Trial 1216, mean bone mineral density (BMD) increased in subjects who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in subjects who remained on FTC/RPV/TDF (0.08% lumbar spine, −0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY subjects and 3.0% of FTC/RPV/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY subjects and 1.2% of FTC/RPV/TDF subjects.

In Trial 1160, mean BMD increased in subjects who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in subjects who remained on EFV/FTC/TDF (−0.05% lumbar spine, −0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY subjects and 4.9% of EFV/FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY subjects and 3.3% of EFV/FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.

Serum Lipids

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.

Table 2 Lipid Values, Mean Change from Baseline Reported in Subjects Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks

	Trial 1216				Trial 1160
	ODEFSEY N=316 [n=235]		FTC/RPV/TDF N=314 [n=245]		ODEFSEY N=438 [n=295]		EFV/FTC/TDF N=437 [n=308]
	Baseline	Week 48	Baseline	Week 48	Baseline	Week 48	Baseline	Week 48
	mg/dL	Changea,b	mg/dL	Changea,b	mg/dL	Changea,b	mg/dL	Changea,b
Total Cholesterol (fasted)	176	+17	171	0	193	-7	192	-3
HDL-Cholesterol (fasted)	50	+3	48	0	56	-4	55	-2
LDL-Cholesterol (fasted)	111	+13	108	+1	118c	-1c	119	-1
Triglycerides (fasted)	116	+12	119	-9	139	-12	133	+3
Total Cholesterol to HDL Ratio	3.7	+0.2	3.8	+0.1	3.7	+0.2	3.8	0

^a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values.
^b Subjects who received lipid-lowering agents during the treatment period were excluded.
^c [n=296] for ODEFSEY group in Study 1160 for LDL-Cholesterol (fasted)

Section 12.4 Microbiology now includes the following

ODEFSEY: Through Week 48, in subjects who switched to ODEFSEY from FTC/RPV/TDF or EFV/FTC/TDF (Trials 1216 (N=316) and 1160 (N=438), respectively), of seven subjects who developed virologic failure, three subjects had detectable NNRTI and/or NRTI resistance substititions at virologic failure that were pre-existing in the baseline sample by proviral DNA sequencing; one of these subjects resuppressed while maintaining ODEFSEY.

The efficacy results from Trials 1216 and 1160 were included in Section 14: Clinical Studies

14    CLINICAL STUDIES

14.1     Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to ODEFSEY

In Trial 1216, the efficacy and safety of switching from emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed HIV-1 infected adults. Subjects were suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen of FTC/RPV/TDF for at least 6 months and have no documented resistance mutations to FTC, TAF, or RPV prior to study entry.  Subjects were randomized in a 1:1 ratio to either switch to ODEFSEY (N=316) once daily or stay on FTC/RPV/TDF (N=314) once daily.  Subjects had a mean age of 45 years (range: 23−72), 90% were male, 75% were White, and 19% were Black.  The mean baseline CD4+ cell count was 709 cells/mm3 (range: 104−2527).

In Trial 1160, the efficacy and safety of switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) to ODEFSEY were evaluated in a randomized, double-blind study of virologically-suppressed HIV-1 infected adults.  Subjects must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen of EFV/FTC/TDF for at least 6 months and have no documented resistance mutations to FTC, TAF, or RPV prior to study entry.  Subjects were randomized in a 1:1 ratio to either switch to ODEFSEY (N=438) once daily or stay on EFV/FTC/TDF (N=437) once daily.  Subjects had a mean age of 48 years (range: 19−76), 87% were male, 67% were White, and 27% were Black.  The mean baseline CD4+ cell count was 700 cells/mm3 (range: 140−1862).

Treatment outcomes of Trials 1216 and 1160 are presented in Table 11.

Table 11 Virologic Outcomes of Trials 1216 and 1160 at Week 48^a in Virologically-Suppressed Subjects who Switched to ODEFSEY

	Study 1216		Study 1160
	ODEFSEY (N=316)	FTC/RPV/TDF (N=313)b	ODEFSEY (N=438)	EFV/FTC/TDF(N=437)
HIV-1 RNA < 50 copies/mL	94%	94%	90%	92%
HIV-1 RNA ≥50 copies/mLc	1%	0%	1%	1%
No Virologic Data at Week 48 Window	6%	6%	9%	7%
Discontinued Study Drug Due to AE or Death and Last Available HIV-1 RNA < 50 copies/mL	2%	1%	3%	1%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mL d	4%	4%	5%	5%
Missing Data During Window but on Study Drug	< 1%	1%	1%	1%

^a Week 48 window was between Day 295 and 378 (inclusive).
^b One subject who was not on FTC/RPV/TDF prior to screening was excluded from the efficacy analysis.
^c Included subjects who had HIV-1 RNA ≥50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
^d Includes subjects who discontinued for reasons other than an AE, death, or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

In addition, section 2.1 was updated to state, “It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ODEFSEY and during therapy in all patients as clinically appropriate.”

Also velpatasvir was added to list of drugs without clinically significant interactions with Odefsey.

The updated labels will soon be available drugs@fda or DailyMed

Steve MorinOffice of Health and Constituent Affairs
Food and Drug Administration

Kimberly StrubleDivision of Antiviral Products
Food and Drug Administration

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

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