Genvoya (Page 2 of 11)

5.5 Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of GENVOYA, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with GENVOYA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

6 ADVERSE REACTIONS

The following adverse drug reactions are discussed in other sections of the labeling:

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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials in Treatment-Naïve Adults

The primary safety assessment of GENVOYA was based on Week 144 pooled data from 1,733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of GENVOYA once daily [see Clinical Studies (14.2)].

The most common adverse reaction (all Grades) reported in at least 10% of subjects in the GENVOYA group was nausea. The proportion of subjects who discontinued treatment with GENVOYA or STRIBILD® due to adverse events, regardless of severity, was 1% and 2%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 5% in the GENVOYA group.

Table 1 Adverse Reactions * (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment-Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)
GENVOYAN=866 STRIBILDN=867
*
Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator.
Nausea 11% 13%
Diarrhea 7% 9%
Headache 6% 5%
Fatigue 5% 4%

The majority of events presented in Table 1 occurred at severity Grade 1.

Clinical Trials in Virologically Suppressed Adults

The safety of GENVOYA in virologically-suppressed adults was based on Week 96 data from 959 subjects in a randomized, open-label, active-controlled trial (Study 109) in which virologically-suppressed subjects were switched from a TDF-containing combination regimen to GENVOYA. Overall, the safety profile of GENVOYA in subjects in this study was similar to that of treatment-naïve subjects [see Clinical Studies (14.3)]. Additional adverse reactions observed with GENVOYA in Study 109 included suicidal ideation, suicidal behavior, and suicide attempt (<1% combined); all of these events were serious and all occurred in subjects with a preexisting history of depression or psychiatric illness.

Clinical Trials in Adult Subjects with Renal Impairment

In an open-label trial (Study 112), 248 HIV-1 infected subjects with estimated creatinine clearance between 30 and 69 mL per minute (by Cockcroft-Gault method) were treated with GENVOYA for a median duration of 144 weeks. Of these subjects, 65% had previously been on a stable TDF-containing regimen. A total of 5 subjects permanently discontinued GENVOYA due to the development of renal adverse events through Week 96. Three of these five were among the 80 subjects with baseline estimated creatinine clearance of less than 50 mL/min and two subjects were among the 162 subjects with baseline estimated creatinine clearance of greater than or equal to 50 mL/min. There were no further renal discontinuations between Weeks 96 and 144. Overall, renally impaired subjects receiving GENVOYA in this study had a mean serum creatinine of 1.5 mg/dL at baseline and 1.4 mg/dL at Week 144. Otherwise, the safety profile of GENVOYA in subjects in this study was similar to that of subjects with normal renal function.

Virologically-Suppressed Adults with End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis

The safety of GENVOYA in subjects with end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis was assessed in 55 subjects (Study 1825) [see Clinical Studies (14.4)]. The most commonly reported adverse reaction (adverse event assessed as causally related by investigator and all grades) was nausea (7%). Serious adverse events were reported in 53% of subjects and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%). Overall 5% of subjects permanently discontinued treatment due to an adverse event.

Renal Laboratory Tests and Renal Safety

Treatment-Naïve Adults:

Cobicistat (a component of GENVOYA) has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred by Week 2 of treatment and remained stable through 144 weeks.

In two 144-week randomized, controlled trials in a total of 1,733 treatment-naïve adults with a median baseline estimated creatinine clearance of 115 mL per minute, mean serum creatinine increased by less than 0.1 mg per dL in the GENVOYA group and by 0.1 mg per dL in the STRIBILD group from baseline to Week 144.

Virologically Suppressed Adults:

In a study of 1,436 virologically-suppressed TDF-treated adults with a mean baseline estimated creatinine clearance of 112 mL per minute who were randomized to continue their treatment regimen or switch to GENVOYA, at Week 96 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to GENVOYA.

Across these trials, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA.

Bone Mineral Density Effects

Treatment-Naïve Adults:

In a pooled analysis of Studies 104 and 111, the effects of GENVOYA compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 144 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 144 was −0.92% with GENVOYA compared to −2.95% with STRIBILD at the lumbar spine and −0.75% compared to −3.36% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known.

Virologically Suppressed Adults:

In Study 109, TDF-treated subjects were randomized to continue their TDF-based regimen or switch to GENVOYA; changes in BMD from baseline to Week 96 were assessed by DXA. Mean BMD increased in subjects who switched to GENVOYA (2.12% lumbar spine, 2.44% total hip) and decreased slightly in subjects who continued their baseline regimen (−0.09% lumbar spine, −0.46% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2% of GENVOYA subjects and 6% of subjects who continued their TDF-based regimen. BMD declines of 7% or greater at the femoral neck were experienced by 2% of GENVOYA subjects and 7% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known.

Laboratory Abnormalities:

The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving GENVOYA in Studies 104 and 111 are presented in Table 2.

Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)
Laboratory Parameter Abnormality * GENVOYAN=866 STRIBILDN=867
*
Frequencies are based on treatment-emergent laboratory abnormalities.
Creatine Kinase (≥10.0 × ULN) 11% 10%
LDL-cholesterol (fasted) (>190 mg/dL) 11% 5%
Total cholesterol (fasted) (>300mg/dL) 4% 3%
Amylase 3% 5%
ALT 3% 3%
AST 3% 4%
Urine RBC (Hematuria) (>75 RBC/HPF) 3% 3%

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 3.

Table 3 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Trials 104 and 111*
GENVOYAN=866 STRIBILDN=867
Baseline Week 144 Baseline Week 144
mg/dL Change mg/dL Change
*
Excludes subjects who received lipid lowering agents during the treatment period.
The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values.
Total Cholesterol (fasted) 162[N=647] +31[N=647] 165[N=627] +14[N=627]
Triglycerides (fasted) 111[N=647] +29[N=647] 115[N=627] +17[N=627]
LDL-cholesterol (fasted) 103[N=647] +20[N=643] 107[N=628] +8[N=628]
HDL-cholesterol (fasted) 47[N=647] +7[N=647] 46[N=627] +3[N=627]
Total Cholesterol to HDL ratio 3.7[N=647] 0.2[N=647] 3.8[N=627] 0.1[N=627]

Clinical Trials in Pediatric Subjects:

Safety in Pediatric Patients

The safety of GENVOYA in HIV-1 infected pediatric subjects was evaluated in treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), and in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=52) through Week 48 (cohort 2) in an open-label clinical trial (Study 106) [see Clinical Studies (14.5)]. With the exception of a decrease in the mean CD4+ cell count observed in cohort 2 of Study 106, the safety profile in pediatric subjects who received treatment with GENVOYA was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.

Bone Mineral Density Effects

Cohort 1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg)

Among the subjects in cohort 1 receiving GENVOYA, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were −0.07 for lumbar spine and −0.20 for TBLH at Week 48. One GENVOYA subject had significant (at least 4%) lumbar spine BMD loss at Week 48.

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Among the subjects in cohort 2 receiving GENVOYA, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. Six GENVOYA subjects had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 subjects also had at least 4% TBLH BMD loss at Week 48.

Change from Baseline in CD4+ cell counts

Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg)

Cohort 2 of Study 106 evaluated pediatric subjects (N=52) who were virologically-suppressed and who switched from their antiretroviral regimen to GENVOYA. Although all subjects had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 4. All subjects maintained their CD4+ cell counts above 400 cells/mm3 [see Pediatric Use (8.4) and Clinical Studies (14.5)].

Table 4 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to GENVOYA
Baseline Mean Change from Baseline
Week 2 Week 4 Week 12 Week 24 Week 32 Week 48
*
Mean (SD)
CD4+ Cell Count (cells/mm3) 961 (275.5)* -117 -114 -112 -118 -62 -66
CD4% 38 (6.4)* +0.3% -0.1% -0.8% -0.8% -1.0% -0.6%

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