Today, November 5, 2015, FDA approved GENVOYA, a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.

GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA.

GENVOYA contains a new form of tenofovir that has not been previously approved. This new form of tenofovir provides lower levels of drug in the bloodstream, but higher levels within the cells where HIV-1 replicates. It was developed to help reduce some drug side effects. GENVOYA appears to be associated with less kidney toxicity and decreases in bone density than previously approved tenofovir containing regimens based on laboratory measures. Patients receiving GENVOYA experienced greater increases in serum lipids (total cholesterol and low-density lipoprotein) than patients receiving other treatment regimens in the studies.

Dosage and Administration:

The recommended dosage of GENVOYA is one tablet taken orally once daily with food.

No dosage adjustment of GENVOYA is required in patients with estimated creatinine clearance greater than or equal to 30 mL per minute.

GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population is insufficient.

GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)

Contraindications:

Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed below.

Drug Class Drugs within Class that are Contraindicated with GENVOYA Clinical Comment
Alpha 1-Adrenoreceptor Antagonist Alfuzosin Potential for increased alfuzosin concentrations, which can result in hypotension.
Anticonvulsants Carbamazepine*

Phenobarbital

Phenytoin

Carbamazepine, phenobarbital, and phenytoin are potent inducers of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect to GENVOYA.
Antimycobacterial Rifampin Rifampin is a potent inducer of CYP450 metabolism and may cause significant decrease in the plasma concentration of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect to GENVOYA.
Ergot Derivatives Dihydroergotamine

Ergotamine

Methylergonovine

Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent Cisapride Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Herbal Products St. John’s wort (Hypericum perforatum) Coadministration of products containing St. John’s wort and GENVOYA may result in reduced plasma concentrations of elvitegravir, cobicistat, and TAF. This may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors Lovastatin

Simvastatin

Potential for serious reactions such as myopathy, including rhabdomyolysis.
Neuroleptic Pimozide Potential for serious and/or life-threatening events such as cardiac arrhythmias.
Phosphodiesterase-5 (PDE5) Inhibitor Sildenafila when dosed as REVATIO for the treatment of pulmonary arterial hypertension There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Sedative/hypnotics Triazolam

Orally administered midazolamb

Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with GENVOYA may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression.

Warnings and Precautions:

The GENVOYA product labeling includes several Warnings and Precautions and are similar to those included in the tenofovir (VIREAD) or STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) labels. The label also includes statements specific to new onset or worsending of renal impairment as follows:

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of GENVOYA, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of GENVOYA in treatment naïve subjects and in virally suppressed subjects switched to GENVOYA with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA. In a study of virally suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with GENVOYA for a median duration of 43 weeks, GENVOYA was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute [see Adverse Reactions
(6.1)]. GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.

Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.

Clinical Trials Experience

Genvoya’s safety and efficacy in adults were evaluated in 3,171 participants enrolled in four clinical trials. Depending on the trial, participants were randomly assigned to receive Genvoya or another FDA approved HIV treatment. Results showed Genvoya was effective in reducing viral loads and comparable to the other treatment regimens.

Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. The safety profile was similar for treatment-naïve and virologically suppressed adults. The safety profile in adolescent subjects was similar to adults. Additionally the safety profile of GENVOYA in subjects with renal impairment was similar to that of subjects with normal renal function. In an open-label trial (Study 112), 248 HIV-1 infected subjects with eGFR of 30 to 69 mL per minute (by Cockcroft-Gault method) were treated with GENVOYA for a median duration of 43 weeks. Of these subjects, 64% had previously been on a stable TDF-containing regimen. Among the 80 subjects with baseline eGFR less than 50 mL per minute receiving GENVOYA, two subjects developed worsening renal impairment and discontinued treatment. One subject with an eGFR over 50 mL per minute developed transient acute renal failure.

Serum Lipids:

Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD.

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 4.

Table 4 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Studies 104 and 111a

GENVOYA

N=866

STRIBILD

N=867

Baseline Week 48 Baseline Week 48
mg/dL Changeb mg/dL Changeb
Total Cholesterol (fasted) 162

[N=757]

+30

[N=757]

166

[N=742]

+13

[N=742]

HDL-cholesterol (fasted) 46

[N=757]

+7

[N=757]

45

[N=742]

+4

[N=742]

LDL-cholesterol (fasted) 104

[N=753]

+15

[N=753]

107

[N=744]

+3

[N=744]

Triglycerides (fasted) 113

[N=757]

+29

[N=757]

119

[N=742]

+10

[N=742]

Total Cholesterol to HDL ratio 3.7

[N=757]

0.2

[N=757]

3.9

[N=742]

0

[N=742]

a. Excludes subjects who received lipid lowering agents during the treatment period.

b.The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values.

Description of Clinical Trials

The efficacy and safety of GENVOYA were evaluated in the studies summarized in the table below

Trials Conducted with GENVOYA in Subjects with HIV-1 Infection

Trial Population Study Arms (N) Timepoint (Week)
Study 104a

Study 111a

Treatment-naïve adults GENVOYA (866)

STRIBILD (867)

48
Study 109b Virologically-suppressedd adults GENVOYA (799)

ATRIPLA® or TRUVADA®+atazanavir+cobicistat or ritonavir or STRIBILD (397)

48
Study 112c Virologically-suppressedd adults with renal impairmente GENVOYA (242) 24
Study 106c Treatment-naïve adolescents between the ages of 12 to less than 18 years GENVOYA (23) 24

a. Randomized, double blind, active controlled trial.
b. Randomized, open label, active controlled trial.
c. Open label trial.
d. HIV-1 RNA less than 50 copies per mL.
e. eGFR of 30 to 69 mL per minute by Cockcroft-Gault method.

Clinical Trial Results in HIV-1 Treatment-Naïve Subjects

In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10 copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3 (range 0-1360) and 13% had CD4+ cell counts less than 200 cells per mm3.

Pooled treatment outcomes of Studies 104 and 111 through 48 weeks are presented in Table 13.

Table 13 Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 48a in Treatment-Naïve Subjects

GENVOYA (N=866) STRIBILD (N=867)
HIV-1 RNA < 50 copies/mL 92% 90%
Treatment Difference 2.0% (95% CI: -0.7% to 4.7%)
HIV-1 RNA ≥ 50 copies/mLb 4% 4%
No Virologic Data at Week 48 Window 4% 6%
Discontinued Study Drug Due to AE or Deathc 1% 2%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 2% 4%
Missing Data During Window but on Study Drug 1% <1%

a.Week 48 window was between Day 294 and 377 (inclusive).

b.Included subjects who had ≥ 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 an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

c.Includes subjects who discontinued due to AE 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 AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.

In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 48 was 230 cells per mm3 in GENVOYA-treated subjects and 211 cells per mm3 in STRIBILD-treated subjects.

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

In Study 109, the efficacy and safety of switching from either ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to GENVOYA once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (1196 of 1436 enrolled and treated were evaluable for efficacy). Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of GENVOYA prior to study entry. Subjects were randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N=799), or stay on their baseline antiretroviral regimen (N=397). Subjects had a mean age of 41 years (range 21-72), 90% were male, 67% were White, and 21% were Black. The mean baseline CD4+ cell count was 705 cells per mm3 (range 79-1951).

Subjects were stratified by prior treatment regimen. At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.

Treatment outcomes of Study 109 through 48 weeks are presented in Table 14.

Table 14 Virologic Outcomes of Study 109 at Week 48a in Virologically-Suppressed Subjects who Switched to GENVOYA

GENVOYA (N=799) ATRIPLA or TRUVADA+atazanavir+cobicistat or ritonavir or STRIBILD (N=397)
HIV-1 RNA < 50 copies/mL 96% 93%
HIV-1 RNA ≥ 50 copies/mLb 1% 1%
No Virologic Data at Week 48 Window 3% 6%
Discontinued Study Drug Due to AE or Deathc 1% 1%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLd 1% 4%
Missing Data During Window but on Study Drug 2% 1%

a. Week 48 window was between Day 294 and 377 (inclusive).

b. Included subjects who had ≥ 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 an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

c. Includes subjects who discontinued due to AE 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 AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization. In Study 109, the mean increase from baseline in CD4+ cell count at Week 48 was 33 cells per mm3 in GENVOYA-treated subjects and 27 cells per mm3 in subjects who stayed on their baseline regimen.

Clinical Trial Results in HIV-1 Infected Subjects with Renal Impairment

In Study 112, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (eGFR of 30 to 69 mL per minute by Cockcroft-Gault method). Of the 248 enrolled, 6 were treatment naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to GENVOYA.

The mean age was 58 years (range 24-82), with 63 subjects (26%) who were 65 years of age or older. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 664 cells per mm3 (range 126-1813). At Week 24, 95% (230/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA. Three subjects had virologic failure at Week 24.

Clinical Trial Results in HIV-1 Treatment-Naïve Adolescent Subjects Aged 12 to Less than 18

In Study 106, the efficacy, safety, and pharmacokinetics of GENVOYA were evaluated in an open-label trial in HIV-1-infected treatment-naïve adolescents aged 12 to less than 18 years. Twenty-three subjects treated with GENVOYA once daily for 24 weeks had a mean age of 14 years; 52% were male, 17% were Asian, and 83% were black. At baseline, mean plasma HIV-1 RNA was 4.8 log10 copies per mL (35% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm3 (range: 104 to 748), and median CD4+ percentage was 23% (range: 7% to 41%).

At 24 weeks, the virologic response rate to GENVOYA in treatment naïve HIV-1 infected adolescents was similar to response rates in trials of treatment naïve HIV-1 infected adults; 91% achieved HIV-1 RNA less than 50 copies per mL. The mean increase from baseline in CD4+ cell count at Week 24 was 212 cells per mm3. Two subjects had virologic failure at Week 24; neither subject had evidence of resistance to GENVOYA.

You can view the complete label at drugs@fda or dailymed.

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

For more information about the HIV Liaison Program visit the FDA Patient Network

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