Darunavir, Cobicistat, Emtricitabine, And Tenofovir Alafenamide

1. INDICATIONS AND USAGE SYMTUZA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. SYMTUZA is a four-drug combination of darunavir (DRV), a human immunodeficiency virus (HIV-1) protease inhibitor, cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg: who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. ( 1 )

2. DOSAGE AND ADMINISTRATION Testing : Prior to or when initiating SYMTUZA, test patients for HBV infection. Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) Recommended dosage : One tablet taken once daily with food in adults and pediatric patients, weighing at least 40 kg. ( 2.2 ) Renal Impairment: SYMTUZA is not recommended in patients with estimated creatinine clearance below 30 mL/min. ( 2.3 ) Hepatic Impairment : SYMTUZA is not recommended in patients with severe hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation of SYMTUZA Prior to or when initiating SYMTUZA, test patients for hepatitis B (HBV) virus infection [see Warnings and Precautions (5.1) ] . Prior to or when initiating SYMTUZA, and during treatment with SYMTUZA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.6) ] . 2.2 Recommended Dosage SYMTUZA is a four-drug fixed-dose combination product containing 800 mg of darunavir (DRV), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of SYMTUZA is one tablet taken orally once daily with food in adults and pediatric patients weighing at least 40 kg. For patients who are unable to swallow the whole tablet, SYMTUZA may be split into two pieces using a tablet-cutter, and the entire dose should be consumed immediately after splitting [see Clinical Pharmacology (12.3) ] . 2.3 Not Recommended in Patients with Severe Renal Impairment SYMTUZA is not recommended in patients with creatinine clearance below 30 mL per minute [see Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Patients with Severe Hepatic Impairment SYMTUZA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) ] . 2.5 Not Recommended During Pregnancy SYMTUZA is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)] . SYMTUZA should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with SYMTUZA.

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) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Severe skin reactions [see Warnings and Precautions (5.3) ] Immune reconstitution syndrome [see Warnings and Precautions (5.5) ] New onset or worsening renal impairment [see Warnings and Precautions (5.6) ] Lactic acidosis/severe hepatomegaly with steatosis [see Warnings and Precautions (5.8) ] The most common adverse reactions (all grades, incidence greater than or equal to 2%) were diarrhea, rash, nausea, fatigue, headache, abdominal discomfort, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Products, LP at 1-800-JANSSEN (1-800-526-7736) 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. Clinical Trials in Adults Adverse Reactions in Adults with No Prior Antiretroviral Treatment History The safety profile of SYMTUZA in HIV-1 infected adults with no prior antiretroviral treatment history is based on Week 48 data from the AMBER trial, a randomized, double-blind, active-controlled trial where a total of 362 subjects received SYMTUZA once daily and 363 subjects received a combination of PREZCOBIX ® (fixed-dose combination of darunavir and cobicistat) and fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). The proportion of subjects who discontinued treatment with SYMTUZA or PREZCOBIX+FTC/TDF due to adverse events, regardless of severity, were 2% and 4% respectively. An overview of the most frequent (occurring in at least 2% of subjects) adverse reactions irrespective of severity reported in AMBER are presented in Table 1. An overview of the most frequent laboratory abnormalities of at least Grade 2 severity reported in AMBER are presented in Table 2. Changes from baseline in lipid parameters for patients receiving SYMTUZA and those receiving PREZCOBIX + FTC/TDF are presented in Table 3. Most adverse reactions during treatment with SYMTUZA were grade 1 or 2 in severity. One grade 3 adverse reaction was reported and no grade 4 adverse reactions were reported during treatment with SYMTUZA. Table 1: Adverse Reactions Reported in ≥2% of HIV-1 Infected Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA (N=362) PREZCOBIX+FTC/TDF (N=363) All Grades At least Grade 2 All Grades At least Grade 2 Diarrhea 9% 2% 11% 2% Rash Includes pooled reported terms: dermatitis, dermatitis allergic, erythema, photosensitivity reaction, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash pruritic, toxic skin eruption, urticaria 8% 4% 7% 5% Nausea 6% 1% 10% 3% Fatigue 4% 1% 4% 1% Headache 3% 1% 2% 1% Abdominal discomfort 2% - 4% <1% Flatulence 2% <1% 1% - Adverse Reactions in Virologically-Suppressed Adults The safety profile of SYMTUZA in virologically-suppressed HIV-1 infected adults is based on Week 48 data from 1,141 subjects in the EMERALD trial, a randomized, open-label, active-controlled trial where 763 subjects with a stable antiretroviral regimen consisting of a boosted protease inhibitor (bPI) [either darunavir once daily or atazanavir (both boosted with ritonavir or cobicistat), or lopinavir with ritonavir] combined with FTC/TDF switched to SYMTUZA, and 378 subjects who continued their treatment regimen of a bPI with FTC/TDF. Overall, the safety profile of SYMTUZA in subjects in this study was similar to that in subjects with no prior antiretroviral treatment history. The proportion of subjects who discontinued treatment with SYMTUZA due to adverse events, regardless of severity, was 1%. Less Frequent Adverse Reactions The following adverse reactions occurred in less than 2% of adults with no antiretroviral treatment history or virologically suppressed subjects receiving SYMTUZA, or are from studies described in the prescribing information of the individual component PREZISTA (darunavir). Gastrointestinal Disorders: dyspepsia, pancreatitis (acute), vomiting Skin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson syndrome Metabolism and Nutrition Disorders: anorexia, diabetes mellitus, lipodystrophy Reproductive System and Breast Disorders: gynecomastia Musculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosis Psychiatric Disorders: abnormal dreams Immune System Disorders: (drug) hypersensitivity, immune reconstitution inflammatory syndrome Hepatobiliary Disorders: acute hepatitis Laboratory Abnormalities Table 2: Laboratory Abnormalities (Grade 2–4) Reported in ≥2% of Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) Laboratory Parameter Grade Limit SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Creatinine Grade 2 >1.3 to 1.8 × ULN 4% 14% Grade 4 ≥3.5× ULN <1% 0 Triglycerides Grade 2 301–500 mg/dL 7% 4% Grade 3 501–1,000 mg/dL 1% 1% Grade 4 >1,000 mg/dL <1% <1% Total Cholesterol Grade 2 240–<300 mg/dL 17% 4% Grade 3 ≥ 300 mg/dL 2% 1% Low-Density Lipoprotein Cholesterol Grade 2 160–189 mg/dL 9% 4% Grade 3 ≥190 mg/dL 5% 1% Elevated Glucose Levels Grade 2 126–250 mg/dL 6% 6% Grade 3 251–500 mg/dL <1% 0 ALT and/or AST elevations (Grade 2–4 combined) occurred in 2% of adult subjects receiving SYMTUZA with no antiretroviral treatment history in AMBER (Week 48 Analysis). Results were consistent in subjects receiving PREZCOBIX+FTC/TDF. Table 3: Lipid Values, Mean Change from Baseline, Reported in Adults With No Prior Antiretroviral Treatment History in AMBER (Week 48 Analysis) SYMTUZA N=362 PREZCOBIX+FTC/TDF N=363 Baseline Week 48 Baseline Week 48 Mean The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values, or the last value carried forward prior to initiating lipid-lowering agent post-baseline. mg/dL Change mg/dL Change N N corresponds to the number of subjects with paired values and not on a lipid-lowering agent at screening/baseline. Subjects on lipid-lowering agents at screening/baseline were excluded from the analysis (6 out of 362 subjects on SYMTUZA, 8 out of 363 subjects on PREZCOBIX+FTC/TDF). Subjects initiating a lipid-lowering agent post-baseline had their last fasted on-treatment value (prior to starting the agent) carried forward (6 on SYMTUZA, 2 on PREZCOBIX+FTC/TDF). N=304 One subject did not have a Week 48 result for LDL cholesterol (n=303). N=290 Total cholesterol 168 +30 164 +11 HDL cholesterol 45 +6 44 +2 LDL cholesterol 100 +19 98 +5 Triglycerides 117 +34 112 +21 Total cholesterol to HDL ratio 4.1 0.2 4.0 0.1 The percentage of subjects starting any lipid lowering drug during treatment in the SYMTUZA and PREZCOBIX + FTC/TDF arm were 1.7% (n=6) and 0.6% (n=2), respectively. Renal Laboratory Tests In the AMBER trial, which enrolled 725 adults with no prior antiretroviral treatment history, subjects had a median baseline eGFR (estimated glomerular filtration rate) of 119 mL/min (SYMTUZA) and 118 mL/min (PREZCOBIX + FTC/TDF). From baseline to Week 48, mean (SD) serum creatinine increased by 0.05 (0.10) mg/dL in the SYMTUZA group and by 0.09 (0.11) mg/dL in the PREZCOBIX + FTC/TDF group. Median serum creatinine was 0.90 mg/dL (SYMTUZA) and 0.89 mg/dL (PREZCOBIX + FTC/TDF) at baseline and 0.95 mg/dL (SYMTUZA) and 0.97 mg/dL (PREZCOBIX +FTC/TDF) at Week 48. Increases in serum creatinine occurred by Week 2 of treatment and remained stable. Median urine protein-to-creatinine ratio (UPCR) was 47 mg/g (SYMTUZA) and 51 mg/g (PREZCOBIX + FTC/TDF) at baseline and 30 mg/g (SYMTUZA) and 34 mg/g (PREZCOBIX + FTC/TDF) at Week 48. In the EMERALD trial which had 1,141 virologically-suppressed adults treated with an HIV protease inhibitor and TDF containing regimen with a median baseline eGFR of 104 mL/min (SYMTUZA) and 103 mL/min (bPI+FTC/TDF) who were randomized to continue their treatment regimen or switch to SYMTUZA, at Week 48, mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to SYMTUZA. Mean (SD) serum creatinine was 0.98 (0.18) mg/dL (SYMTUZA) and 0.98 (0.19) mg/dL (bPI+FTC/TDF) at baseline and 0.99 (0.18) mg/dL (SYMTUZA) and 0.99 (0.21) mg/dL (bPI+FTC/TDF) at Week 48. Median serum creatinine was 0.97 mg/dL (SYMTUZA) and 0.98 mg/dL (bPI+FTC/TDF) at baseline and 1.0 mg/dL (SYMTUZA) and 0.97 mg/dL (bPI+FTC/TDF) at Week 48. Median UPCR was 62 mg/g (SYMTUZA) and 63 mg/g (bPI+FTC/TDF) at baseline and 37 mg/g (SYMTUZA) and 53 mg/g (bPI+FTC/TDF) at Week 48. Bone Mineral Density AMBER The effects of SYMTUZA compared to PREZCOBIX + FTC/TDF on bone mineral density (BMD) change from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 48 was −0.7% with SYMTUZA compared to −2.4% with PREZCOBIX + FTC/TDF at the lumbar spine and 0.2% compared to −2.7% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 16% of SYMTUZA subjects and 22% of PREZCOBIX + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 2% of SYMTUZA subjects and 15% of PREZCOBIX + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. EMERALD In EMERALD, bPI and TDF-treated subjects were randomized to continue their TDF-based regimen or switch to SYMTUZA; changes in BMD from baseline to Week 48 were assessed by DXA. The mean percentage change in BMD from baseline to Week 48 was 1.5% with SYMTUZA compared to −0.6% with bPI + FTC/TDF at the lumbar spine and 1.4% compared to -0.3% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of SYMTUZA subjects and 9% of bPI + FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by no SYMTUZA subjects and 2% of bPI + FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known. Clinical Trials in Pediatric Patients Adverse Reactions in Pediatric Patients Weighing At Least 40 kg No clinical trials with SYMTUZA were performed in pediatric patients. However, the safety of the components of SYMTUZA was evaluated in pediatric subjects of 12 to less than 18 years of age through clinical trials GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) for darunavir co-administered with cobicistat and other antiretroviral agents, and GS-US-292-0106 (treatment-naïve, N=50 with weight ≥35 kg) for a fixed-dose combination regimen containing cobicistat, emtricitabine, and tenofovir alafenamide together with elvitegravir. Safety analyses of the trials in these pediatric subjects did not identify new safety concerns compared to the known safety profile of SYMTUZA in adult subjects [see Clinical Studies (14.3) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of darunavir. 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. Metabolism and Nutrition Disorders: Redistribution of body fat Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors) Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3) ] Renal and Urinary Disorders: Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, Fanconi syndrome [see Warnings and Precautions (5.6) ] , crystal nephropathy, and crystalluria

12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The bioavailability of the components of SYMTUZA was not affected when administered orally as a split tablet compared to administration as a tablet swallowed whole. Pharmacokinetic (PK) properties and PK parameters of the components of SYMTUZA are provided in Table 5 and Table 6, respectively. Table 5: Pharmacokinetic Properties of the Components of SYMTUZA Darunavir Cobicistat Emtricitabine TAF PBMCs = peripheral blood mononuclear cells; CES-1 = carboxylesterase-1 Absorption T max (h) 3.0 3.0 1.5 0.5 Effect of high-fat meal Approximately 928 kcal; 504 kcal from fat (56 g), 260 kcal from carbohydrates, and 164 kcal from protein. (compared to fasting) AUC last LS mean ratio, 90% CI 1.52 (1.32–1.76) 1.41 (1.02–1.96) 1.00 (0.96–1.04) 1.12 (1.01–1.23) C max LS mean ratio, 90% CI 1.82 (1.55–2.14) 1.30 (0.94–1.80) 0.79 (0.71–0.89) 0.55 (0.42–0.71) Distribution % bound to human plasma proteins 95 Primarily alpha-1-acid glycoprotein 97–98 <4 ~80 Source of protein binding data In vitro In vitro In vitro Ex vivo Blood-to-plasma ratio 0.64 0.5 0.6 1.0 Metabolism Metabolism CYP3A CYP3A (major) CYP2D6 (minor) Not significantly metabolized Cathepsin A In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon co-administration with the moderate CYP3A inducer probe efavirenz, TAF exposure was unaffected. (PBMCs) CES1 (hepatocytes) CYP3A (minimal) Elimination t 1/2 (h) 9.4 3.2 7.5 0.5 Note that the pharmacologically active metabolite tenofovir diphosphate has a half-life of 150–180 hours within PBMCs. Tenofovir in plasma has a median elimination half-life of approximately 44 hours. Major route of elimination Metabolism Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose) % of dose excreted in feces Dosing in mass balance studies: darunavir (single dose administration of [ 14C] darunavir co-administered with multiple dose ritonavir 100 mg); cobicistat (single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14C] TAF). 79.5 Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. 86.2 13.7 31.7 % of dose excreted in urine 13.9 8.2 70 <1 Table 6: Steady State Pharmacokinetic Parameters of Darunavir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of SYMTUZA with Food in HIV-Infected Adults Parameter Mean (SD) Darunavir Cobicistat From Phase 2 PK substudy (N=21) Emtricitabine TAF Tenofovir C max , ng/mL 8826 (33.3) 1129 (35.3) 2056 (25.3) 163 (51.9) 18.8 (37.6) AUC 24h , ng.h/mL 87909 (20232) From population PK analysis in SYMTUZA Phase 3 study TMC114FD2HTX3001 in ARV naïve subjects (N=355) 85972 (22413) From population PK analysis in SYMTUZA Phase 3 study TMC114IFD3013 in ARV experienced subjects (N=750) 8745 (43.9) 11918.0 (35.9) 132 (41) 339 (37.1) C 0h , ng/mL 1899 (759) 1813 (859) 31 (135) 93.1 (58.3) NA 11.7 (39.3) Specific Populations Geriatric Patients Darunavir : Pharmacokinetic analysis in HIV-infected subjects taking darunavir co-administered with cobicistat, emtricitabine, and tenofovir alafenamide showed no considerable differences in darunavir pharmacokinetics for ages below or equal to 65 years compared to ages greater than 65 years (N=25). Cobicistat and Emtricitabine : The pharmacokinetics of cobicistat and emtricitabine have not been fully evaluated in the elderly (65 years of age and older). Tenofovir alafenamide Population pharmacokinetics analysis of HIV-infected subjects in Phase 2 and Phase 3 trials of TAF combined with emtricitabine, elvitegravir, and cobicistat showed that age did not have a clinically relevant effect on exposures of TAF up to 75 years of age. Pediatric Patients Weighing at Least 40 kg Available pharmacokinetic data for the different components of SYMTUZA indicate that there were no clinically relevant differences in exposure between adults and pediatric subjects weighing at least 40 kg. Darunavir and cobicistat : In pediatric subjects aged 12 to less than 18 years, weighing at least 40 kg who received darunavir 800 mg co-administered with cobicistat 150 mg (N=7), geometric mean darunavir C max values were similar between adults and pediatric subjects. Geometric mean darunavir AUC 24h and C 24h values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in pediatric subjects relative to adults, respectively. These differences were not considered clinically significant. Geometric mean cobicistat AUC 24h , C max , and C 24h values were comparable in pediatric subjects and adults (Table 7). Table 7: Multiple-Dose PK Parameters of Darunavir and Cobicistat Following Administration of Darunavir with Cobicistat in HIV 1 Infected Adults and Pediatric Subjects Weighing at least 40 kg From intensive PK analysis of trial GS-US-216-0128, where HIV-infected subjects were administered darunavir 800 mg and cobicistat 150 mg once daily with 2 NRTIs Parameter Geometric mean (CV%) Darunavir Cobicistat CV = Coefficient of Variation; mcg = microgram Pediatric Subjects N=7 N=7 AUC 24h (mcg.hr/mL) 77.22 (29.5) 8.33 (34.9) C max (mcg/mL) 7.32 (21.7) 1.10 (20.0) C 24h (mcg/mL) 0.68 (91.6) 0.02 (123.9) N=5; Data from two subjects who had undetectable cobicistat C 24h concentrations were excluded from summary statistics Adults From intensive PK analysis of trial GS-US-299-0102 where HIV-infected subjects were administered SYMTUZA once daily N=21 N=21 AUC 24h (mcg.hr/mL) 90.56 (45.3) 7.69 (43.9) C max (mcg/mL) 8.34 (33.3) 1.04 (35.3) C 24h (mcg/mL) 1.00 (108.0) 0.02 (135.1) N=18 Emtricitabine and tenofovir alafenamide : In 24 pediatric subjects aged 12 to less than 18 years, who received emtricitabine + TAF with elvitegravir + cobicistat, geometric mean emtricitabine C max , and C 24h values were comparable to adults, with geometric mean ratios of 1.10 (90% CI: 0.98, 1.23) and 1.07 (90% CI: 0.88, 1.29), respectively (Table 8). Geometric mean emtricitabine AUC 24h was 21% higher, with a geometric mean ratio of 1.21 (90% CI: 1.09, 1.34) in pediatric subjects relative to adults. Geometric mean tenofovir alafenamide C max and AUC last values were 29% and 23% lower in pediatric subjects versus adults with geometric mean ratios of 0.71 (90% CI: 0.50, 1.00) and 0.77 (90% CI: 0.59, 1.02), respectively (Table 8). The observed differences were not considered clinically significant. Table 8: Multiple-Dose PK Parameters of Emtricitabine and Tenofovir Alafenamide Following Oral Administration with Food in HIV 1 Infected Adults and Pediatric Subjects Parameter Geometric mean (CV%) Emtricitabine Tenofovir alafenamide CV = Coefficient of Variation; mcg = microgram; NA = not applicable Pediatric Subjects From intensive PK analysis in trial GS-US-292-0106 in treatment-naïve pediatric subjects with HIV-1 infection N=24 N=24 AUC 24h (mcg.hr/mL) AUC last for tenofovir alafenamide 14.0 (23.9) 0.16 (55.8) C max (mcg/mL) 2.2 (22.5) 0.14 (64.4) C 24h (mcg/mL) 0.10 (38.9) N=23 NA Adults From intensive PK analysis in trial GS-US-292-0102 in HIV-infected adults treated with emtricitabine+tenofovir alafenamide and elvitegravir+cobicistat N=19 N=19 AUC 24h (mcg.hr/mL) 11.6 (16.6) 0.21 (47.3) C max (mcg/mL) 2.0 (20.2) 0.19 (64.6) C 24h (mcg/mL) 0.09 (46.7) NA Gender and Race There were no clinically relevant differences in the pharmacokinetics of darunavir, cobicistat, emtricitabine, or tenofovir alafenamide based on gender or race. Patients with Renal Impairment Darunavir : The pharmacokinetics of darunavir were not altered in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, estimated by Cockcroft-Gault method, N=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end-stage renal disease taking darunavir co-administered with cobicistat [see Use in Specific Populations (8.6) ] . Cobicistat : There were no clinically relevant differences in cobicistat pharmacokinetics observed between subjects with severe renal impairment (creatinine clearance below 30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects [see Use in Specific Populations (8.6) ] . Emtricitabine : Mean systemic emtricitabine exposure was higher in patients with severe renal impairment (creatinine clearance less than 30 mL/min, estimated by Cockcroft-Gault method) than in subjects with normal renal function [see Use in Specific Populations (8.6) ] . Tenofovir alafenamide : In studies of TAF, no clinically relevant differences in the pharmacokinetics of TAF or its metabolite tenofovir were observed between subjects with severe renal impairment (creatinine clearance of 15–30 mL/min, estimated by Cockcroft-Gault method) and healthy subjects [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment Darunavir : There were no clinically relevant differences in the pharmacokinetics of darunavir (600 mg with ritonavir 100 mg twice daily) in subjects with mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8), compared to subjects with normal hepatic function (n=16). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.7) ] . Cobicistat : There were no clinically relevant differences in the cobicistat pharmacokinetics between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. The effect of severe hepatic impairment on the pharmacokinetics of cobicistat has not been evaluated [see Use in Specific Populations (8.7) ] . Emtricitabine : The pharmacokinetics of emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited [see Use in Specific Populations (8.7) ] . Tenofovir Alafenamide : Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild, moderate (Child-Pugh Class A and B), or severe hepatic impairment (Child-Pugh Class C); [see Use in Specific Populations (8.7) ] . Patients with Hepatitis B and/or Hepatitis C Virus Coinfection Darunavir : In HIV-infected subjects taking darunavir co-administered with ritonavir, the 48-week analysis of the data from clinical trials indicated that hepatitis B and/or hepatitis C virus coinfection status had no apparent effect on the exposure of darunavir. Cobicistat : There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat. Emtricitabine and tenofovir alafenamide : The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Pregnancy and Postpartum The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 9 and Figure 1 ). Table 9: Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy, and Postpartum Pharmacokinetics of total darunavir (mean ± SD) 2 nd Trimester of pregnancy N=7 3 rd Trimester of pregnancy N=6 Postpartum (6–12 weeks) N=6 C max , ng/mL 4340 ± 1616 4910 ± 970 7918 ± 2199 AUC 24h , ng.h/mL 47293 ± 19058 47991 ± 9879 99613 ± 34862 C min , ng/mL 168 ± 149 184 ± 99 1538 ± 1344 Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd and 3 rd Trimester of Pregnancy Compared to Postpartum Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e., second or third trimester/postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25. Figure 1 Drug Interactions Darunavir is metabolized by CYP3A. Cobicistat is metabolized by CYP3A and, to a minor extent, by CYP2D6. Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data. Emtricitabine is not an inhibitor of human CYP450 enzymes. In vitro and clinical drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A. It is not an inhibitor or inducer of CYP3A in vivo . A drug-drug interaction study between darunavir/cobicistat and dabigatran etexilate was conducted in healthy participants. The effects of darunavir on co-administration with dabigatran etexilate are summarized in Table 10. Table 10: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of darunavir/cobicistat Dose/Schedule LS Mean ratio (90% CI) of co-administered drug pharmacokinetic parameters with/without darunavir no effect =1.00 Co-administered drug Co-administered drug Darunavir/ cobicistat N PK C max AUC C min N = number of subjects with data q.d. = once daily Dabigatran etexilate 150 mg 800/150 mg single dose 14 ↑ 2.64 (2.29–3.05) 2.64 (2.32–3.00) - 800/150 mg q.d. 800/150 mg q.d. for 14 days before co-administered with dabigatran etexilate. 14 ↑ 1.99 (1.72–2.30) 1.88 (1.65–2.13) -