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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbation of Hepatitis B [see Warnings and Precautions (5.1) ] New Onset or Worsening of Renal Impairment [see Warnings and Precautions (5.3) ] Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.4) ] Most common adverse reaction (incidence greater than or equal to 10%, all grades) is headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Adverse Reactions in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease The safety assessment of VEMLIDY was based on pooled data through the Week 96 data analysis from 1298 subjects in two randomized, double-blind, active-controlled trials, Trial 108 and Trial 110, in adult subjects with chronic hepatitis B and compensated liver disease. A total of 866 subjects received VEMLIDY 25 mg once daily [see Clinical Studies (14.2) ] . Further safety assessment was based on pooled data from Trials 108 and 110 from subjects who continued to receive their original blinded treatment through Week 120 and additionally from subjects who received open-label VEMLIDY from Week 96 through Week 120 (n = 361 remained on VEMLIDY; n = 180 switched from TDF to VEMLIDY at Week 96). Based on the Week 96 analysis, the most common adverse reaction (all Grades) reported in at least 10% of subjects in the VEMLIDY group was headache. The proportion of subjects who discontinued treatment with VEMLIDY or TDF due to adverse reactions of any severity was 1.5% and 0.9%, respectively. Table 1 displays the frequency of the adverse reactions (all Grades) greater than or equal to 5% in the VEMLIDY group. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (All Grades) Reported in ≥5% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis Double-blind phase. ) VEMLIDY (N=866) TDF (N=432) Headache 12% 10% Abdominal pain Grouped term including abdominal pain upper, abdominal pain, abdominal pain lower, and abdominal tenderness. 9% 6% Cough 8% 8% Back pain 6% 6% Fatigue 6% 5% Nausea 6% 6% Arthralgia 5% 6% Diarrhea 5% 5% Dyspepsia 5% 5% Additional adverse reactions occurring in less than 5% of subjects in Trials 108 and 110 included vomiting, rash, and flatulence. The safety profile of VEMLIDY in subjects who continued to receive blinded treatment through Week 120 was similar to that at Week 96. The safety profile of VEMLIDY in subjects who remained on VEMLIDY in the open-label phase through Week 120 was similar to that in subjects who switched from TDF to VEMLIDY at Week 96. Renal Laboratory Tests In a pooled analysis of Trials 108 and 110 in adult subjects with chronic hepatitis B and a median baseline estimated creatinine clearance between 106 and 105 mL per minute (for the VEMLIDY and TDF groups, respectively), mean serum creatinine increased by less than 0.1 mg/dL and median serum phosphorus decreased by 0.1 mg/dL in both treatment groups at Week 96. Median change from baseline to Week 96 in estimated creatinine clearance was -1.2 mL per minute in the VEMLIDY group and -4.8 mL per minute in those receiving TDF. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, change from baseline in renal laboratory parameter values in each group at Week 120 were similar to those at Week 96. In the open-label phase, median change in estimated creatinine clearance by Cockcroft-Gault method from Week 96 to Week 120 was -0.6 mL per minute in subjects who remained on VEMLIDY and +1.8 mL per minute in those who switched from TDF to VEMLIDY at Week 96. Mean serum creatinine and median serum phosphorus values at Week 120 were similar to those at Week 96 in subjects who remained on VEMLIDY and in subjects who switched from TDF to VEMLIDY. The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between VEMLIDY and TDF is not known. Bone Mineral Density Effects In a pooled analysis of Trials 108 and 110, the mean percentage change in bone mineral density (BMD) from baseline to Week 96 as assessed by dual-energy X-ray absorptiometry (DXA) was -0.7% with VEMLIDY compared to -2.6% with TDF at the lumbar spine and -0.3% compared to -2.5% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 11% of VEMLIDY subjects and 25% of TDF subjects at Week 96. BMD declines of 7% or greater at the femoral neck were experienced by 5% of VEMLIDY subjects and 13% of TDF subjects at Week 96. In subjects who remained on blinded treatment beyond Week 96 in Trials 108 and 110, mean percentage change in BMD in each group at Week 120 was similar to that at Week 96. In the open-label phase, mean percentage change in BMD from Week 96 to Week 120 in subjects who remained on VEMLIDY was 0.6% at the lumbar spine and 0% at the total hip, compared to 1.7% at the lumbar spine and 0.6% at the total hip in those who switched from TDF to VEMLIDY. 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 VEMLIDY in Trials 108 and 110 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Subjects with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis Double-blind phase. ) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. VEMLIDY (N=866) TDF (N=432) ULN=Upper Limit of Normal ALT (>5 × ULN) 8% 10% LDL-cholesterol (fasted) (>190 mg/dL) 6% 1% Glycosuria (≥3+) 5% 2% AST (>5 × ULN) 3% 5% Creatine Kinase (≥10 × ULN) 3% 3% Serum Amylase (>2.0 × ULN) 3% 3% The overall incidence of blinded treatment ALT flares (defined as confirmed serum ALT greater than 2 × baseline and greater than 10 × ULN at 2 consecutive postbaseline visits, with or without associated symptoms) was similar between VEMLIDY (0.6%) and TDF (0.9%) through Week 96. ALT flares generally were not associated with coincident elevations in bilirubin, occurred within the first 12 weeks of treatment, and resolved without recurrence. Based on the Week 120 analysis, the frequencies of lab abnormalities in subjects who remained on VEMLIDY in the open-label phase were similar to those in subjects who switched from TDF to VEMLIDY at Week 96. Amylase and Lipase Elevations and Pancreatitis At Week 96, in Trials 108 and 110, eight subjects treated with VEMLIDY with elevated amylase levels had associated symptoms, such as nausea, low back pain; abdominal tenderness, pain, and distension; and biliary pancreatitis and pancreatitis. Of these eight, two subjects discontinued VEMLIDY due to elevated amylase and/or lipase; one subject experienced recurrence of adverse events when VEMLIDY was restarted. No subject treated with TDF had associated symptoms or discontinued treatment. From Week 96 to Week 120, one additional subject who continued open-label VEMLIDY and none of the subjects who switched from TDF to VEMLIDY had elevated amylase levels and associated symptoms. Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among subjects treated with VEMLIDY and TDF in Trials 108 and 110 are presented in Table 3. Table 3 Lipid Abnormalities: Mean Change from Baseline in Lipid Parameters in Patients with Chronic HBV Infection and Compensated Liver Disease in Trials 108 and 110 (Week 96 analysis) VEMLIDY (N=866) TDF (N=432) Baseline Week 96 Baseline Week 96 mg/dL Change The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 96 values. mg/dL Change Total Cholesterol (fasted) 188 [n=835] -1 [n=742] 193 [n=423] -25 [n=368] HDL-Cholesterol (fasted) 60 [n=835] -5 [n=740] 61 [n=423] -12 [n=368] LDL-Cholesterol (fasted) 116 [n=835] +7 [n=741] 120 [n=423] -10 [n=368] Triglycerides (fasted) 102 [n=836] +13 [n=743] 102 [n=423] -7 [n=368] Total Cholesterol to HDL ratio 3 [n=835] 0 [n=740] 3 [n=423] 0 [n=368] In the open-label phase, lipid parameters at Week 120 in subjects who remained on VEMLIDY were similar to those at Week 96. In subjects who switched from TDF to VEMLIDY, mean change from Week 96 to Week 120 in total cholesterol was 23 mg/dL, HDL-cholesterol was 5 mg/dL, LDL-cholesterol was 16 mg/dL, triglycerides was 30 mg/dL, and total cholesterol to HDL ratio was 0 mg/dL. Adverse Reactions in Virologically Suppressed Adult Subjects with Chronic Hepatitis B The safety of VEMLIDY in virologically suppressed adults is based on Week 48 data from a randomized, double-blind, active-controlled trial (Trial 4018) in which subjects taking TDF at baseline were randomized to switch to VEMLIDY (N=243) or to continue their TDF treatment (N=245). Adverse reactions observed with VEMLIDY in Trial 4018 were similar to those in Trials 108 and 110 [see Clinical Studies (14.3) ]. Renal Laboratory Tests, Bone Mineral Density Effects, and Serum Lipids In virologically suppressed adults in Trial 4018, changes from baseline in renal function, BMD, and lipid parameters in the VEMLIDY and TDF groups at Week 48 were similar to those observed in Trials 108 and 110 at Week 96. Adverse Reactions in Adult Subjects with Chronic Hepatitis B and Renal Impairment In an open-label trial (Trial 4035) in virologically suppressed adult subjects with chronic hepatitis B switching to VEMLIDY 25 mg, the safety of VEMLIDY was assessed in 78 subjects with moderate to severe renal impairment (estimated creatinine clearance between 15 and 59 mL per minute by Cockcroft-Gault method; Part A, Cohort 1) and 15 subjects with ESRD (estimated creatinine clearance below 15 mL per minute) receiving chronic hemodialysis (Part A, Cohort 2). The safety of VEMLIDY, including changes from baseline in renal function, BMD, and lipid parameters, was similar to that observed in clinical trials of VEMLIDY in subjects with compensated liver disease but without renal impairment [see Use in Specific Populations (8.6) and Clinical Studies (14.4) ]. Adverse Reactions in Pediatric Subjects with Chronic Hepatitis B The safety of VEMLIDY was evaluated in HBV-infected treatment-naïve and treatment-experienced pediatric subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (Cohort 1; N=70) and 6 to less than 12 years and weighing at least 25 kg (Cohort 2, Group 1: N=18) through Week 24 in a randomized, double-blind, placebo-controlled clinical trial (Trial 1092). Subjects were then eligible to roll over to receive open-label VEMLIDY. Safety data are available through Week 96 [see Clinical Studies (14.5) ]. The safety profile of VEMLIDY was similar to that in adults. Bone Mineral Density Effects Among the Cohort 1 and Cohort 2, Group 1 subjects treated with VEMLIDY and placebo, the mean percent change in BMD from baseline to Week 24 was 1.6% (N=48) and 1.9% (N=23) for lumbar spine, and 1.9% (N=50) and 2.0% (N=23) for whole body, respectively. At Week 24, mean changes from baseline BMD Z-scores were 0.01 and -0.07 for lumbar spine, and -0.04 and -0.04 for whole body, for the VEMLIDY and placebo groups, respectively. At Week 24, BMD declines of 4% or greater at lumbar spine and whole body were experienced by 6% and 2% of VEMLIDY subjects, respectively. In the open-label phase, mean percentage change in lumbar spine and whole body BMD and BMD Z-scores from baseline to Week 96 was similar in subjects who remained on VEMLIDY compared to those who switched from placebo to VEMLIDY. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of VEMLIDY or other products containing tenofovir alafenamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Angioedema, urticaria Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome