Darunavir Ethanolate And Cobicistat

1 INDICATIONS AND USAGE PREZCOBIX is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). PREZCOBIX is a two-drug combination of darunavir, a human immunodeficiency virus (HIV-1) protease inhibitor, and cobicistat, a CYP3A inhibitor, and is indicated for the treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V). ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended dosage: One tablet taken once daily with food in adults and pediatric patients weighing at least 40 kg. ( 2.1 ) Testing Prior to Initiation: HIV genotypic testing is recommended for antiretroviral treatment experienced patients. Assess estimated creatinine clearance in all patients prior to starting PREZCOBIX. When used with tenofovir DF: Assess urine glucose and urine protein at baseline and monitor creatinine clearance, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. ( 2.2 ) 2.1 Recommended Dosage PREZCOBIX is a fixed-dose combination product containing 800 mg of darunavir and 150 mg of cobicistat. In treatment-naïve and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions, the recommended dosage of PREZCOBIX is one tablet taken once daily orally with food. Administer PREZCOBIX in conjunction with other antiretroviral agents. 2.2 Testing Prior to Initiation of PREZCOBIX HIV Genotypic Testing HIV genotypic testing is recommended for antiretroviral treatment-experienced patients. However, when HIV genotypic testing is not feasible, PREZCOBIX can be used in protease inhibitor-naïve patients, but is not recommended in protease inhibitor-experienced patients. Creatinine Clearance Prior to starting PREZCOBIX, assess estimated creatinine clearance because cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3) ] . When co-administering PREZCOBIX with tenofovir disoproxil fumarate (tenofovir DF) assess estimated creatinine clearance, urine glucose, and urine protein at baseline [see Warnings and Precautions (5.4) ] . 2.3 Not Recommended in Severe Renal Impairment PREZCOBIX co-administered with tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL per minute [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ] . 2.4 Not Recommended in Severe Hepatic Impairment PREZCOBIX is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.5 Not Recommended During Pregnancy PREZCOBIX 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) ] . PREZCOBIX should not be initiated in pregnant individuals. An alternative regimen is recommended for those who become pregnant during therapy with PREZCOBIX.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ] Severe skin reactions [see Warnings and Precautions (5.2) ] Effects on serum creatinine [see Warnings and Precautions (5.3) ] New onset or worsening renal impairment when used with tenofovir DF [see Warnings and Precautions (5.4) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.10) ] The most common adverse reactions to darunavir, a component of PREZCOBIX (incidence greater than or equal to 5%) of at least moderate severity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting. ( 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 clinical practice. Clinical Trials in Adults During the darunavir clinical development program, where darunavir was co-administered with ritonavir 100 mg once or twice daily, the most common clinical adverse reactions (incidence greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, headache, abdominal pain, and vomiting. See the darunavir full prescribing information for additional information on adverse reactions reported with darunavir co-administered with ritonavir. See cobicistat full prescribing information for clinical trial information on adverse reactions reported with cobicistat. One single arm clinical trial was conducted with darunavir and cobicistat administered as single entities in 313 subjects with HIV-1 infection. Adverse reactions evaluated through Week 24 did not differ substantially from those reported in clinical trials with darunavir co-administered with ritonavir. Clinical Trials in Pediatric Patients No clinical trials with PREZCOBIX were performed in pediatric patients. However, the safety of the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside reverse transcriptase inhibitors, was evaluated in pediatric subjects of 12 to less than 18 years of age with HIV-1 infection through clinical trial GS-US-216-0128 (virologically-suppressed, N=7 with weight ≥40 kg) through Week 48. Safety analyses of this trial in these pediatric subjects did not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult subjects [see Clinical Studies (14.2) ] . 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) Renal and Urinary Disorders Crystal nephropathy, crystalluria Skin and Subcutaneous Tissue Disorders Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.2) ] .

12.3 Pharmacokinetics The pharmacokinetics of darunavir co-administered with cobicistat (150 mg) have been evaluated in healthy adult subjects and in HIV-1 infected subjects. Darunavir is primarily metabolized by CYP3A. Cobicistat inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. Under fed (535 total kcal, 171 kcal from fat, 268 kcal from carbohydrates, 96 kcal from protein) and fasted conditions in healthy subjects, the 90% confidence intervals when comparing darunavir exposure between PREZCOBIX and darunavir 800 mg co-administered with cobicistat 150 mg as single entities were within 80–125%. Darunavir exposure when comparing darunavir co-administered with cobicistat (as single entities) to darunavir co-administered with ritonavir was evaluated in a relative bioavailability trial [see cobicistat full prescribing information]. Table 2 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir 800 mg co-administered with ritonavir 100 mg once daily (based on sparse sampling in 335 subjects in Trial TMC114-C211 and 280 subjects in Trial TMC114-C229) and darunavir 800 mg co-administered with cobicistat 150 mg once daily administered as single entities (based on sparse sampling in 298 subjects in Trial GS-US-216-0130) to HIV-1 infected subjects. Table 2: Population Pharmacokinetic Estimates of Darunavir as Darunavir 800 mg Co-administered with Ritonavir 100 mg Once Daily (Trial TMC114-C211, 48 Week Analysis and Trial TMC114-C229, 48 Week Analysis) and Darunavir 800 mg Co-administered with Cobicistat 150 mg Once Daily (Trial GS-US-216-130, 24 Week Analysis) Trial TMC114-C211 (treatment-naïve) Darunavir 800 mg co-administered with ritonavir 100 mg once daily Trial TMC114-C229 (treatment-experienced) Darunavir 800 mg co-administered with ritonavir 100 mg once daily Trial GS-US-216-0130 (treatment-naïve and experienced) Darunavir 800 mg co-administered with cobicistat 150 mg once daily Parameter N=335 N=280 N=298 N=number of subjects with data AUC 24h (ng∙h/mL) Mean ± Standard Deviation 93026 ± 27050 93334 ± 28626 100152 ± 32042 Median (Range) 87854 (45000–219240) 87788 (45456–236920) 96900 (34500–224000) C 0h (ng/mL) Mean ± Standard Deviation 2282 ± 1168 2160 ± 1201 2043 ± 1257 Median (Range) 2041 (368–7242) 1896 (184–7881) 1875 (70–6890) Absorption and Bioavailability In healthy subjects, under fed conditions, when single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the maximum plasma concentration was achieved within approximately 4 to 4.5 hours for darunavir and approximately 4 to 5 hours for cobicistat. Effects of Food on Oral Absorption When compared to fasted conditions, administration of PREZCOBIX to healthy adult subjects with a high-fat meal (965 total kcal: 129 kcal from protein, 236 kcal from carbohydrates and 600 kcal from fat) resulted in a 70% increase in AUC (0–inf) and a 127% increase in C max for darunavir. Cobicistat exposures were not affected by food. PREZCOBIX should be taken with food. Distribution Darunavir : Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG). Cobicistat : Cobicistat is 97–98% bound to human plasma proteins and the mean blood–to-plasma ratio was approximately 0.5. Metabolism Darunavir : In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14 C-darunavir co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1. Cobicistat : Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. Elimination Darunavir : A mass balance trial in healthy subjects showed that after single dose administration of 400 mg 14 C-darunavir co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14 C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of darunavir was approximately 7 hours under fed conditions. Cobicistat : When single doses of the darunavir and cobicistat fixed-dose combination tablet were administered, the terminal elimination half-life of cobicistat was approximately 4 hours under fed conditions. With single dose administration of 14 C-cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively. Specific Populations Hepatic Impairment Darunavir : Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir 600 mg co-administered with ritonavir 100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child-Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Use in Specific Populations (8.6) ]. Cobicistat : Cobicistat is primarily metabolized by the liver. A trial evaluating the pharmacokinetics of cobicistat was performed in non-HIV-1 infected subjects with moderate hepatic impairment. No clinically relevant differences in cobicistat pharmacokinetics were observed 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 (8.6) ]. Hepatitis B or Hepatitis C Virus Co-Infection Darunavir : In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, the 48 week analysis of the data from clinical studies in HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir. The effect of hepatitis B and/or C virus infection on the pharmacokinetics of PREZCOBIX have not been evaluated. Renal Impairment Darunavir : Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1 infected subjects with moderate renal impairment taking darunavir co-administered with ritonavir (creatinine clearance between 30–60 mL/min, 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-adminstered with either ritonavir or cobicistat [see Use in Specific Populations (8.7) ]. Cobicistat : A trial of the pharmacokinetics of cobicistat was performed in non-HIV infected subjects with severe renal impairment (estimated creatinine clearance below 30 mL/min). No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment and healthy subjects [see Use in Special Populations (8.7) ]. Gender Darunavir : In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1 infected females compared to males. This difference is not clinically relevant. Cobicistat : No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat. Race Darunavir : Population pharmacokinetic analysis of darunavir in HIV-1 infected subjects taking darunavir co-administered with ritonavir indicated that race had no apparent effect on the exposure to darunavir. Cobicistat : Population pharmacokinetic analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat. Geriatric Patients Darunavir : In subjects with HIV-1 infection taking darunavir co-administered with ritonavir, population pharmacokinetic analysis showed no considerable differences in darunavir pharmacokinetics for ages 18 to 75 years compared to ages greater than or equal to 65 years (n=12) [ see Use in Specific Populations (8.5) ] . Cobicistat : Insufficient data are available to determine whether potential differences exist in the pharmacokinetics of cobicistat in geriatric (65 years of age and older) subjects compared to younger subjects. Pediatric Patients Weighing at Least 40 kg Available pharmacokinetic data for the different components of PREZCOBIX 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 3). Table 3: 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 subjects with HIV-1 infection 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 subjects with HIV-1 infection were administered darunavir/cobicistat/emtricitabine/tenofovir alafenamide 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 Pregnancy and Postpartum The exposure to total and unbound darunavir boosted with cobicistat after intake of PREZCOBIX 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 4 and Figure 1 ). Table 4: Pharmacokinetic Results of Total Darunavir after Administration of PREZCOBIX 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 PREZCOBIX 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 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 [see Drug Interactions (7) ] . 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 5. Table 5: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of darunavir/cobicistat Co-administered drug Dose/Schedule N PK LS Mean ratio (90% CI) of co-administered drug pharmacokinetic parameters with/without darunavir no effect =1.00 Co-administered drug Darunavir/ cobicistat 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) -