DESCOVY

1 INDICATIONS AND USAGE HIV-1 Treatment ( 1.1 ): DESCOVY is a two-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and adolescent patients weighing at least 35 kg. for the treatment of HIV-1 infection in pediatric patients weighing at least 14 kg to less than 35 kg in combination with other antiretroviral agents, including darunavir and cobicistat but not other protease inhibitors that require a CYP3A inhibitor. HIV-1 PrEP ( 1.2 ): DESCOVY is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sexual acquisition, excluding individuals at risk from receptive vaginal sex. Individuals must have a negative HIV-1 test immediately prior to initiating DESCOVY for HIV-1 PrEP. Limitations of Use ( 1.2 ): The indication does not include use of DESCOVY in individuals at risk of HIV-1 from receptive vaginal sex because effectiveness in this population has not been evaluated. 1.1 Treatment of HIV-1 Infection DESCOVY is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and adolescent patients weighing at least 35 kg. DESCOVY is indicated for the treatment of HIV-1 infection in pediatric patients weighing at least 14 kg to less than 35 kg in combination with other antiretroviral agents, including darunavir and cobicistat but not other protease inhibitors that require a CYP3A inhibitor. 1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP) DESCOVY is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sexual acquisition, excluding individuals at risk from receptive vaginal sex. Individuals must have a negative HIV-1 test immediately prior to initiating DESCOVY for HIV-1 PrEP [see Dosage and Administration (2.2) and Warnings and Precautions (5.2) ]. Limitations of Use: The indication does not include use of DESCOVY in individuals at risk of HIV-1 from receptive vaginal sex because effectiveness in this population has not been evaluated [see Clinical Studies (14.3) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [see Warnings and Precautions (5.1) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.3) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.5) ]. In participants with HIV-1, the most common adverse reaction (incidence greater than or equal to 10%, all grades) was nausea. ( 6.1 ) In adults without HIV-1 in a PrEP trial, the most common adverse reaction (incidence greater than or equal to 5%, all grades) was diarrhea. ( 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 (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 FTC+TAF with Elvitegravir (EVG) plus Cobicistat (COBI) in Treatment-Naïve Adults with HIV-1 In pooled 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reaction in participants treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of participants discontinued FTC+TAF with EVG+COBI due to adverse events during the 48-week treatment period [see Clinical Studies (14.2) ] . The safety profile was similar in virologically-suppressed adults with HIV-1 who were switched to FTC+TAF with EVG+COBI (N=799). Antiretroviral treatment-naïve adult participants with HIV-1 treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol, and 29 mg/dL of triglycerides after 48 weeks of use. Renal Laboratory Tests In two 48-week trials in antiretroviral treatment-naïve adults with HIV-1 treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Median urine protein-to-creatinine ratio (UPCR) was 44 mg per gram at baseline and at Week 48. In a 48-week trial in virologically-suppressed TDF-treated adults with HIV-1 who switched to FTC+TAF with EVG+COBI (N=959) with a mean baseline eGFR of 112 mL per minute, mean serum creatinine was similar to baseline at Week 48; median UPCR was 61 mg per gram at baseline and 46 mg per gram at Week 48. Across these trials, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a 24-week trial in adults with HIV-1 and renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. Median UPCR was 161 mg per gram at baseline and 93 mg per gram at Week 24. FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) participants. Bone Mineral Density Effects In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 −1.30% with FTC+TAF with EVG+COBI at the lumbar spine and −0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI participants. The long-term clinical significance of these BMD changes is not known. In 799 virologically-suppressed TDF-treated adult participants with HIV-1 that switched to FTC+TAF with EVG+COBI, at Week 48 mean BMD increased (1.86% lumbar spine, 1.95% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 1% of FTC+TAF with EVG+COBI participants. Adverse Reactions in a Clinical Trial of FTC+TAF with EVG+COBI in Virologically-Suppressed Adults with HIV-1 and End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis In a 48-week trial of virologically-suppressed adult participants with HIV-1 and end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis treated with FTC+TAF with EVG+COBI (N=55), 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 participants and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%). Overall 5% of participants permanently discontinued treatment due to an adverse event. Adverse Reactions in Clinical Trials in Pediatric Participants with HIV-1 Study 106: Adverse Reactions in a Clinical Trial of FTC+TAF with EVG+COBI in Pediatric Participants Weighing at Least 25 kg The safety profile of FTC+TAF in pediatric participants weighing at least 25 kg is informed by an open-label trial of antiretroviral treatment-naïve pediatric participants with HIV-1 between the ages of 12 to less than 18 years weighing at least 35 kg through 48 weeks (N=50; cohort 1) and virologically-suppressed participants with HIV-1 between the ages of 6 to less than 12 years weighing at least 25 kg (N=52; cohort 2). Participants received FTC+TAF with EVG+COBI through 48 weeks. With the exception of a decrease in the mean CD4+ cell count observed in cohort 2, the safety of this combination was similar to that in adults. Bone Mineral Density Effects Cohort 1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg) Among the participants in cohort 1 receiving FTC+TAF with EVG+COBI, 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 participant 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 participants in cohort 2 receiving FTC+TAF with EVG+COBI, 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 participants had significant (at least 4%) lumbar spine BMD loss at Week 48 and 2 participants 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 evaluated pediatric participants (N=52) who were virologically-suppressed and who switched from their antiretroviral regimen to FTC+TAF with EVG+COBI. Although all participants 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 2 . All participants maintained their CD4+ cell counts above 400 cells/mm 3 [see Use in Specific Populations (8.4) ]. Table 2 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Participants from 6 to <12 Years Who Switched to FTC+TAF with EVG+COBI Mean Change from Baseline Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 (275.5) Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 (6.4) +0.3% -0.1% -0.8% -0.8% -1.0% -0.6% Study 1474: Adverse Reactions in a Clinical Trial of FTC+TAF with Bictegravir in Pediatric Participants Weighing at Least 14 to Less Than 25 kg In a separate open-label trial of virologically-suppressed participants at least 2 years of age and weighing at least 14 to less than 25 kg (N=22; cohort 3) who received FTC+TAF with bictegravir through 24 weeks, no new adverse reactions or laboratory abnormalities were identified compared to those observed in adults. In this trial, the mean (SD) change from baseline to Week 24 in CD4+ cell count was −126 (264) cells per mm 3 and the mean (SD) change in CD4% from baseline to Week 24 was 0.2% (4.4%). Study 128: Adverse Reactions in a Clinical Trial of DESCOVY in combination with Darunavir+Cobicistat (DRV+COBI) in Pediatric Participants Weighing at Least 14 kg The safety profile of DESCOVY is also informed by a separate open-label trial of virologically-suppressed pediatric participants between the ages of 6 to less than 12 years and weighing at least 25 to less than 40 kg (N=9; cohort 2), and virologically-suppressed pediatric participants at least 2 years of age and weighing at least 14 to less than 25 kg (N=11; cohort 3) who received DESCOVY in combination with DRV+COBI through Week 48. In this study, the safety profile of DESCOVY was similar to that in adults. Bone Mineral Density Effects Cohort 2: Pediatric Participants Weighing at Least 25 to Less Than 40 kg Among the participants in cohort 2 who had both baseline and Week 48 measurements (n=8 and 9 for lumbar spine and TBLH, respectively), mean BMD increased from baseline to Week 48, +6.1% at lumbar spine and +4.4% for TBLH. Cohort 3: Pediatric Participants Weighing at Least 15 to less Than 25 kg Among the participants in cohort 3 who had both baseline and Week 48 measurements (n=7 and 10 for lumbar spine and TBLH, respectively), mean BMD increased from baseline to Week 48, +8.7% at lumbar spine and +6.9% for TBLH. Adverse Reactions from Clinical Trial Experience in Individuals without HIV-1 Taking DESCOVY for HIV-1 PrEP The safety profile of DESCOVY for HIV-1 PrEP was comparable to that observed in clinical trials of participants with HIV based on a double-blind, randomized, active-controlled trial (DISCOVER) in which a total of 5,387 adult men and transgender women without HIV-1 who have sex with men received DESCOVY (N=2,694) or TRUVADA (N=2,693) once daily for HIV-1 PrEP [see Clinical Studies (14.3) ] . Median duration of exposure was 86 and 87 weeks, respectively. The most common adverse reaction in participants who received DESCOVY (incidence greater than or equal to 5%, all grades) was diarrhea (5%). Table 3 provides a list of the most common adverse reactions that occurred in 2% or more of participants in either treatment group. The proportion of participants who discontinued treatment with DESCOVY or TRUVADA due to adverse events, regardless of severity, was 1.3% and 1.8%, respectively. Table 3 Adverse Reactions (All Grades) Reported in ≥2% in Either Arm in the DISCOVER Trial of Participants without HIV-1 DESCOVY (N=2,694) TRUVADA (N=2,693) Diarrhea 5% 6% Nausea 4% 5% Headache 2% 2% Fatigue 2% 3% Abdominal pain Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain, and abdominal discomfort 2% 3% Renal Laboratory Tests Changes from baseline to Week 48 in renal laboratory data are presented in Table 4 . The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between DESCOVY and TRUVADA is not known. Table 4 Laboratory Assessments of Renal Function Reported in Participants without HIV-1 Receiving DESCOVY or TRUVADA in the DISCOVER Trial DESCOVY (N=2,694) TRUVADA (N=2,693) eGFR CG =estimated Glomerular Filtration Rate by Cockcroft-Gault; UPCR=urine protein/creatinine ratio Serum Creatinine (mg/dL) Mean (SD). Change at Week 48 −0.01 (0.107) 0.01 (0.111) eGFR CG (mL/min) Median (Q1, Q3). Change at Week 48 1.8 (−7.2, 11.1) −2.3 (−10.8, 7.2) Percentage of Participants who Developed UPCR >200 mg/g Based on N who had normal UPCR (≤ 200 mg/g) at baseline. At Week 48 0.7% 1.5% Bone Mineral Density Effects In the DISCOVER trial, mean increases from baseline to Week 48 of 0.5% at the lumbar spine (N=159) and 0.2% at the total hip (N=158) were observed in participants receiving DESCOVY, compared to mean decreases of 1.1% at the lumbar spine (N=160) and 1.0% at the total hip (N=158) in participants receiving TRUVADA. BMD declines of 5% or greater at the lumbar spine and 7% or greater at the total hip were experienced by 4% and 1% of participants, respectively, in both treatment groups at Week 48. The long-term clinical significance of these BMD changes is not known. Serum Lipids Changes from baseline to Week 48 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 5 . Table 5 Fasting Lipid Values, Mean Change from Baseline, Reported in Participants without HIV-1 Receiving DESCOVY or TRUVADA in the DISCOVER Trial Excludes participants who received lipid lowering agents during the treatment period. DESCOVY (N=2,694) TRUVADA (N=2,693) Baseline Week 48 Baseline Week 48 mg/dL Change The baseline and change from baseline are for participants with both baseline and Week 48 values. mg/dL Change Total Cholesterol (fasted) 176 N=1,098 0 176 N=1,124 -12 HDL-Cholesterol (fasted) 51 -2 51 -5 LDL-Cholesterol (fasted) 103 N=1,079 0 103 N=1,107 -7 Triglycerides (fasted) 109 +9 111 -1 Total Cholesterol to HDL ratio 3.7 0.2 3.7 0.1 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of products containing TAF. 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, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome