CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Darunavir is an HIV-1 antiviral drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn thorough QT/QTc study in 40 healthy subjects, darunavir/ritonavir doses of 1.33 times the maximum recommended dose did not affect the QT/QTc interval.. 12.3 Pharmacokinetics. Pharmacokinetics in AdultsGeneral:Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When single dose of darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and darunavir/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients. Table 11: Population Pharmacokinetic Estimates of Darunavir at Darunavir/Ritonavir 800/100 mg Once Daily (Trial TMC114-C211, 48-Week Analysis and Trial TMC114-C229, 48-Week Analysis) and Darunavir/Ritonavir 600/100 mg Twice Daily (Trial TMC114-C214, 48-Week Analysis, Trial TMC114-C229, 48-Week Analysis and Integrated Data from Trials TMC114-C213 and TMC114-C202, Primary 24-Week Analysis) N=number of subjects with dataaAUC24h is calculated as AUC12h2. Parameter Darunavir/Ritonavir 800/100 mg once daily Darunavir/Ritonavir 600/100 mg twice daily TMC114-C211 N=335 TMC114-C229 N=280 TMC114-C214 N=285 TMC114-C229 N=278 TMC114-C213 TMC114-C202 (integrated data) N=119 AUC24h (ng.h/mL)a Mean +- Standard Deviation 93026 +- 27050 93334 +- 28626 116796 +- 33594 114302 +- 32681 124698 +- 32286 Median (Range) 87854 (45000 to 219240) 87788 (45456 to 236920) 111632 (64874 to 355360) 109401 (48934 to 323820) 123336 (67714 to 212980) C0h (ng/mL) Mean +- Standard Deviation 2282 +- 1168 2160 +- 1201 3490 +- 1401 3386 +- 1372 3578 +- 1151 Median (Range) 2041 (368 to 7242) 1896 (184 to 7881) 3307 (1517 to 13198) 3197 (250 to 11865) 3539 (1255 to 7368) Absorption and BioavailabilityDarunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with Tmax of approximately 2.5 to hours. The absolute oral bioavailability of single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.Effects of Food on Oral AbsorptionWhen darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).Distribution:Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).Metabolism: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. mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 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.Elimination:A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-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. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.. Special PopulationsHepatic Impairment:Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir/ritonavir 600/100 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 Dosage and Administration (2.6) and Use in Specific Populations (8.6)].Hepatitis or Hepatitis Virus Co-infection:The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1 infected subjects indicated that hepatitis and/or hepatitis virus co-infection status had no apparent effect on the exposure of darunavir.Renal Impairment:Results from mass balance study with 14C- darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-1- infected subjects with moderate renal impairment (CrCL between 30 to 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 [see Use in Specific Populations (8.7)].Gender:Population pharmacokinetic analysis showed higher mean darunavir exposure in HIV-1-infected females compared to males. This difference is not clinically relevant.Race:Population pharmacokinetic analysis of darunavir in HIV-1-infected subjects indicated that race had no apparent effect on the exposure to darunavir.Geriatric Patients:Population pharmacokinetic analysis in HIV-1-infected subjects showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-1-infected subjects (n=12, age greater than or equal to 65) [see Use in Specific Populations (8.5)].Pediatric Patients:Darunavir/Ritonavir Administered Twice DailyThe pharmacokinetics of darunavir in combination with ritonavir in 93 antiretroviral treatment- experienced HIV-1-infected pediatric subjects to less than 18 years of age and weighing at least 10 kg showed that the administered weight-based dosages resulted in similar darunavir exposure when compared to the darunavir exposure achieved in treatment-experienced adults receiving darunavir/ritonavir 600/100 mg twice daily [see Dosage and Administration (2.5)].Darunavir/Ritonavir Administered Once DailyThe pharmacokinetics of darunavir in combination with ritonavir in 12 antiretroviral treatment-naive HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 40 kg receiving darunavir/ritonavir 800/100 mg once daily resulted in similar darunavir exposures when compared to the darunavir exposure achieved in treatment-naive adults receiving darunavir/ritonavir 800/100 mg once daily [see Dosage and Administration (2.5)].Based on population pharmacokinetic modeling and simulation, the proposed darunavir/ritonavir once daily dosing regimens for pediatric patients to less than 12 years of age is predicted to result in similar darunavir exposures when compared to the darunavir exposures achieved in treatment-naive adults receiving darunavir/ritonavir 800/100 mg once daily [see Dosage and Administration (2.5)].The population pharmacokinetic parameters in pediatric subjects with darunavir/ritonavir administered once or twice daily are summarized in the table below: Table 12: Population Pharmacokinetic Estimates of Darunavir Exposure (Trials TMC114-C230, TMC114-C212 and TMC114-C228) Following Administration of Doses in Table N number of subjects with data.a Summary statistics for population pharmacokinetic parameter estimates for DRV after administration of DRV/rtv at 800/100 mg once daily in treatment-naive HIV-1 infected subjects from 12 to 18 years of age -Week-48 Analyses.b Calculated from individual pharmacokinetic parameters estimated for Week and Week 4, based on the Week 48 analysis that evaluated darunavir dose of 20 mg/kg twice daily with ritonavir mg/kg twice daily.c Subjects may have contributed pharmacokinetic data to both the 10 kg to less than 15 kg weight group and the 15 kg to less than 20 kg weight group.d The 15 kg to less than 20 kg weight group received 380 mg (3.8 mL) darunavir oral suspension twice daily with 48 mg (0.6 mL) ritonavir oral solution twice daily in TMC114-C228. Calculated from individual pharmacokinetic parameters estimated for Week post-dose adjustment visit; Week 24 and Week 48 based on the Week 48 analysis that evaluated darunavir dose of 380 mg twice daily.e AUC24h is calculated as AUC12h2 Darunavir/Ritonavir Once Daily Darunavir/Ritonavir Twice Daily TMC114-C230a TMC114-C212 TMC114-C228c Parameter N=12 N=74 10 to less than 15 kgb N=10 15 to less than 20 kgd N=13 AUC24h (ngh/mL)e Mean +- Standard Deviation 84390 +- 23587 126377 +- 34356 137896 +- 51420 157760 +- 54080 Median (Range) 86741 (35527 to 123325) 127340 (67054 to 230720) 124044 (89688 to 261090) 132698 (112310 to 294840) C0h (ng/mL) Mean +- Standard Deviation 2141 +- 865 3948 +- 1363 4510 +- 2031 4848 +- 2143 Median (Range) 2234 (542 to 3776) 3888 (1836 to 7821) 4126 (2456 to 9361) 3927 (3046 to 10292) Pregnancy and PostpartumThe exposure to total darunavir and ritonavir after intake of darunavir/ritonavir 600/100 mg twice daily and darunavir/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Table 13, Table 14 and Figure 1). Table 13: Pharmacokinetic Results of Total Darunavir After Administration of Darunavir/Ritonavir at 600/100 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum n=11 for AUC24hb AUC24h is calculated asAUC12h2 Pharmacokinetics of total darunavir (mean +- standard deviation) 2nd Trimester of pregnancy (n=12)a 3rd Trimester of pregnancy (n=12) Postpartum (6 to 12 Weeks) (n=12) Cmax ng/mL 4668 +- 1097 5328 +- 1631 6659 +- 2364 AUC24h ng.h/mLb 78740 +- 19194 91760 +- 34720 113780 +- 52680 Cmin ng/mL 1922 +- 825 2661 +- 1269 2851 +- 2216 Table 14: Pharmacokinetic Results of Total Darunavir After Administration of Darunavir/Ritonavir at 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum Pharmacokinetics of total darunavir (mean +- standard deviation) 2nd Trimester of pregnancy (n=17) 3rd Trimester of pregnancy (n=15) Postpartum (6 to 12 Weeks) (n=16) Cmax ng/mL 4964 +- 1505 5132 +- 1198 7310 +- 1704 AUC24h ng.h/mL 62289 +- 16234 61112 +- 13790 92116 +- 29241 Cmin ng/mL 1248 +- 542 1075 +- 594 1473 +- 1141 Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1).Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir After Administration of Darunavir/Ritonavir at 600/100 mg Twice Daily or 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to PostpartumImageLegend: 90% CI: 90% confidence interval; GMR: geometric mean ratio. Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.. Drug Interactions[See also Contraindications (4), Warnings and Precautions (5.5) and Drug Interactions (7).]Darunavir co-administered with ritonavir is an inhibitor of CYP3A, CYP2D6, and P-gp. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A and CYP2D6, or are transported by P-gp, may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events.Darunavir and ritonavir are metabolized by CYP3A. In vitro data indicate that darunavir may be P-gp substrate. Drugs that induce CYP3A activity would be expected to increase the clearance of darunavir and ritonavir, resulting in lowered plasma concentrations of darunavir and ritonavir. Co-administration of darunavir and ritonavir and other drugs that inhibit CYP3A or P-gp may decrease the clearance of darunavir and ritonavir and may result in increased plasma concentrations of darunavir and ritonavir.Drug interaction studies were performed with darunavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax, and Cmin values are summarized in Table 15 (effect of other drugs on darunavir) and Table 16 (effect of darunavir on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).Several interaction studies have been performed with dose other than the recommended dose of the co-administered drug or darunavir; however, the results are applicable to the recommended dose of the co-administered drug and/or darunavir. Table 15: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-Administered Drugs = number of subjects with data.a q.d. once daily.b b.i.d. twice daily.c The pharmacokinetic parameters of darunavir in this study were compared with the pharmacokinetic parameters following administration of darunavir/ritonavir 600/100 mg twice daily. Ratio based on between-study comparison. q.o.d. every other day Dose/Schedule LS Mean ratio (90% CI) of Darunavir Pharmacokinetic Parameters With/Without Co-Administered Drug No Effect =1.00 Co-administered Drug Co-administered Drug Darunavir/ Ritonavir PK Cmax AUC Cmin Co-administration with other HIV protease inhibitors Atazanavir 300 mg q.d.a 400/100 mg b.i.d.b 13 <-> 1.02 (0.96 to 1.09) 1.03 (0.94 to 1.12) 1.01 (0.88 to 1.16) Indinavir 800 mg b.i.d. 400/100 mg b.i.d. 1.11 (0.98 to 1.26) 1.24 (1.09 to 1.42) 1.44 (1.13 to 1.82) Lopinavir/ritonavir 400/100 mg b.i.d. 533/133.3 mg b.i.d. 1200/100 mg b.i.d.c 1200 mg b.i.d.c 14 15 0.79 (0.67 to 0.92) 0.79 (0.64 to 0.97) 0.62 (0.53 to 0.73) 0.59 (0.50 to 0.70) 0.49 (0.39 to 0.63) 0.45 (0.38 to 0.52) Saquinavir hard gel capsule 1000 mg b.i.d. 400/100 mg b.i.d. 14 0.83 (0.75 to 0.92) 0.74 (0.63 to 0.86) 0.58 (0.47 to 0.72) Co-administration with other HIV antiretrovirals Didanosine 400 mg q.d. 600/100 mg b.i.d. 17 <-> 0.93 (0.86 to 1.00) 1.01 (0.95 to 1.07) 1.07 (0.95 to 1.21) Efavirenz 600 mg q.d. 300/100 mg b.i.d. 12 0.85 (0.72 to 1.00) 0.87 (0.75 to 1.01) 0.69 (0.54 to 0.87) Etravirine 200 mg b.i.d. 600/100 mg b.i.d. 15 <-> 1.11 (1.01 to 1.22) 1.15 (1.05 to 1.26) 1.02 (0.90 to 1.17) Nevirapine 200 mg b.i.d. 400/100 mg b.i.d. 1.40d (1.14 to 1.73) 1.24d (0.97 to 1.57) 1.02d (0.79 to 1.32) Rilpivirine 150 mg q.d. 800/100 mg q.d. 15 <-> 0.90 (0.81 to 1.00) 0.89 (0.81 to 0.99) 0.89 (0.68 to 1.16) Tenofovir disoproxil fumarate 300 mg q.d. 300/100 mg b.i.d. 12 1.16 (0.94 to 1.42) 1.21 (0.95 to 1.54) 1.24 (0.90 to 1.69) Co-administration with other drugs Artemether/lumefantrine 80/480 mg (6 doses at 0, 8,24, 36, 48, and60 hours) 600/100 mg b.i.d. 14 <-> 1.00 (0.93 to 1.07) 0.96 (0.90 to 1.03) 0.87 (0.77 to 0.98) Carbamazepine 200 mg b.i.d. 600/100 mg b.i.d. 16 <-> 1.04 (0.93 to 1.16) 0.99 (0.90 to 1.08) 0.85 (0.73 to 1.00) Clarithromycin 500 mg b.i.d. 400/100 mg b.i.d. 17 <-> 0.83 (0.72 to 0.96) 0.87 (0.75 to 1.01) 1.01 (0.81 to 1.26) Ketoconazole 200 mg b.i.d. 400/100 mg b.i.d. 14 1.21 (1.04 to 1.40) 1.42 (1.23 to 1.65) 1.73 (1.39 to 2.14) Omeprazole 20 mg q.d. 400/100 mg b.i.d. 16 <-> 1.02 (0.95 to 1.09) 1.04 (0.96 to 1.13) 1.08 (0.93 to 1.25) Paroxetine 20 mg q.d. 400/100 mg b.i.d. 16 <-> 0.97 (0.92 to 1.02) 1.02 (0.95 to 1.10) 1.07 (0.96 to 1.19) Pitavastatin mg q.d. 800/100 mg q.d. 27 <-> 1.06 (1.00 to 1.12) 1.03 (0.95 to 1.12) NA Ranitidine 150 mg b.i.d. 400/100 mg b.i.d. 16 <-> 0.96 (0.89 to 1.05) 0.95 (0.90 to 1.01) 0.94 (0.90 to 0.99) Rifabutin 150 mg q.o.d.e 600/100 mg b.i.d. 11 1.42 (1.21 to 1.67) 1.57 (1.28 to 1.93) 1.75 (1.28 to 2.37) Sertraline 50 mg q.d. 400/100 mg b.i.d. 13 <-> 1.01 (0.89 to 1.14) 0.98 (0.84 to 1.14) 0.94 (0.76 to 1.16) Table 16: Drug Interactions: Pharmacokinetic Parameters for Co-Administered Drugs in the Presence of Darunavir/Ritonavir = number of subjects with data;-= no information availablea q.d. once dailyb b.i.d. twice dailyc The pharmacokinetic parameters of lopinavir in this study were compared with the pharmacokinetic parameters following administration of lopinavir/ritonavir 400/100 mg twice daily.d Noted as or C24 in the dolutegravir U.S. prescribing informatione ratio is for buprenorphine; mean Cmax and AUC24 for naloxone were comparable when buprenorphine/naloxone was administered with or without darunavir/ritonavirf800/100 mg q.d. for 14 days before co-administered with dabigatran etexilate.g q.o.d. every other dayh In comparison to rifabutin 300 mg once daily. 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/ Ritonavir PK Cmax AUC min Co-administration with other HIV protease inhibitors Atazanavir 300 mg q.d.a /100 mg ritonavir q.d. when administered alone 300 mg q.d. when administered with darunavir/ ritonavir 400/100 mg b.i.d.b 13 <-> 0.89 (0.78 to 1.01) 1.08 (0.94 to 1.24) 1.52 (0.99 to 2.34) Indinavir 800 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone 800 mg b.i.d. when administered with darunavir/ ritonavir 400/100 mg b.i.d. 1.08 (0.95 to 1.22) 1.23 (1.06 to 1.42) 2.25 (1.63 to 3.10) Lopinavir/ritonavir 400/100 mg b.i.d.c 533/133.3 mg b.i.d.c 1200/100 mg b.i.d. 1200 mg b.i.d. 14 15 <-> <-> 0.98 (0.78 to 1.22) 1.11 (0.96 to 1.30) 1.09 (0.86 to 1.37) 1.09 (0.96 to 1.24) 1.23 (0.90 to 1.69) 1.13 (0.90 to 1.42) Saquinavir hard gel capsule 1000 mg b.i.d. /100 mg ritonavir b.i.d. when administered alone 1000 mg b.i.d. when administered with darunavir/ ritonavir 400/100 mg b.i.d. 12 <-> 0.94 (0.78 to 1.13) 0.94 (0.76 to 1.17) 0.82 (0.52 to 1.30) Co-administration with other HIV antiretrovirals Didanosine 400 mg q.d. 600/100 mg b.i.d. 17 <-> 0.84 (0.59 to 1.20) 0.91 (0.75 to 1.10) Dolutegravir 30 mg q.d 600/100 mg b.i.d. 15 0.89 (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62d (0.56 to 0.69) Dolutegravir 50 mg q.d. 600/100 mg b.i.d. with 200 mg b.i.d. etravirine 0.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63d (0.52 to 0.76) Efavirenz 600 mg q.d. 300/100 mg b.i.d. 12 1.15 (0.97 to 1.35) 1.21 (1.08 to 1.36) 1.17 (1.01 to 1.36) Etravirine 100 mg b.i.d. 600/100 mg b.i.d. 14 0.68 (0.57 to 0.82) 0.63 (0.54 to 0.73) 0.51 (0.44 to 0.61) Nevirapine 200 mg b.i.d. 400/100 mg b.i.d. 1.18 (1.02 to 1.37) 1.27 (1.12 to 1.44) 1.47 (1.20 to 1.82) Rilpivirine 150 mg q.d. 800/100 mg q.d. 14 1.79 (1.56 to 2.06) 2.30 (1.98 to 2.67) 2.78 (2.39 to 3.24) Tenofovir disoproxil fumarate 300 mg q.d. 300/100 mg b.i.d. 12 1.24 (1.08 to 1.42) 1.22 (1.10 to 1.35) 1.37 (1.19 to 1.57) Maraviroc 150 mg b.i.d. 600/100 mg b.i.d. 12 2.29 (1.46 to 3.59) 4.05 (2.94 to 5.59) 8.00 (6.35 to 10.1) 600/100 mg b.i.d. with 200 mg b.i.d. etravirine 10 1.77 (1.20 to 2.60) 3.10 (2.57 to 3.74) 5.27 (4.51 to 6.15) Co-administration with other drugs Atorvastatin 40 mg q.d. when administered alone 10 mg q.d. when administered with darunavir/ritonavir 300/100 mg b.i.d. 15 0.56 (0.48 to 0.67) 0.85 (0.76 to 0.97) 1.81 (1.37 to 2.40) Artemether 80 mg single dose 600/100 mg b.i.d. 15 0.85 (0.68 to 1.05) 0.91 (0.78 to 1.06) Dihydroartemisinin 15 1.06 (0.82 to 1.39) 1.12 (0.96 to 1.30) Artemether artemether/ lumefantrine 600/100 mg b.i.d. 15 0.82 (0.61 to 1.11) 0.84 (0.69 to 1.02) 0.97 (0.90 to 1.05) Dihydroartemisinin 80/480 mg (6 doses at 0, 8,24, 15 0.82 (0.66 to 1.01) 0.82 (0.74 to 0.91) 1.00 (0.82 to 1.22) Lumefantrine 36, 48, and 60 hours) 15 1.65 (1.49 to 1.83) 2.75 (2.46 to 3.08) 2.26 (1.92 to 2.67) Buprenorphine/ Naloxone Norbuprenorphine 8/2 mg to 16/4 mg q.d. 600/100 mg b.i.d. 17 17 <-> 0.92 (0.79 to 1.08) 1.36 (1.06 to 1.74) 0.89 (0.78 to 1.02) 1.46 (1.15 to 1.85) 0.98 (0.82 to 1.16) 1.71 (1.29 to 2.27) Carbamazepine Carbamazepine epoxide 200 mg b.i.d. 600/100 mg b.i.d. 16 16 1.43 (1.34 to 1.53) 0.46 (0.43 to 0.49) 1.45 (1.35 to 1.57) 0.46 (0.44 to 0.49) 1.54 (1.41 to 1.68) 0.48 (0.45 to 0.51) Clarithromycin 500 mg b.i.d. 400/100 mg b.i.d. 17 1.26 (1.03 to 1.54) 1.57 (1.35 to 1.84) 2.74 (2.30 to 3.26) Dabigatran etexilate 150 mg 800/100 mg single dose 800/100 mg q.d.f 14 13 1.64 (1.212.23) 1.22 (0.891.67) 1.72 (1.332.23) 1.18 (0.901.53) - Dextromethorphan Dextrorphan 30 mg 600/100 mg b.i.d. 12 2.27 (1.59 to 3.26) 0.87 (0.77 to 0.98) 2.70 (1.80 to 4.05) 0.96 (0.90 to 1.03) - Digoxin 0.4 mg 600/100 mg b.i.d. 1.15 (0.89 to 1.48) 1.36 (0.81 to 2.27) Ethinyl estradiol (EE) Norethindrone (NE) Ortho-Novum 1/35 (35 mcg EE /1 mg NE) 600/100 mg b.i.d. 11 11 0.68 (0.61 to 0.74) 0.90 (0.83 to 0.97) 0.56 (0.50 to 0.63) 0.86 (0.75 to 0.98) 0.38 (0.27 to 0.54) 0.70 (0.51 to 0.97) Ketoconazole 200 mg b.i.d. 400/100 mg b.i.d. 15 2.11 (1.81 to 2.44) 3.12 (2.65 to 3.68) 9.68 (6.44 to 14.55) R-Methadone 55 to 150 mg q.d. 600/100 mg b.i.d. 16 0.76 (0.71 to 0.81) 0.84 (0.78 to 0.91) 0.85 (0.77 to 0.94) Omeprazole 5-hydroxy omeprazole 40 mg single dose 600/100 mg b.i.d. 12 0.66 (0.48 to 0.90) 0.93 (0.71 to 1.21) 0.58 (0.50 to 0.66) 0.84 (0.77 to 0.92) - Paroxetine 20 mg q.d. 400/100 mg b.i.d. 16 0.64 (0.59 to 0.71) 0.61 (0.56 to 0.66) 0.63 (0.55 to 0.73) Pitavastatin mg q.d. 800/100 mg q.d. 27 0.96 (0.84 to 1.09) 0.74 (0.69 to 0.80) NA Pravastatin 40 mg single dose 600/100 mg b.i.d. 14 1.63 (0.95 to 2.82) 1.81 (1.23 to 2.66) Rifabutin 25-O -desacetyl rifabutin 150 mg q.o.d. gwhen administered with darunavir ritonavir 300 mg q.d. when administered alone 600/100 mg b.i.d.h 11 11 0.72 (0.55 to 0.93) 4.77 (4.04 to 5.63) 0.93 (0.80 to 1.09) 9.81 (8.09 to 11.9) 1.64 (1.48 to 1.81) 27.1 (22.2 to 33.2) Sertraline 50 mg q.d. 400/100 mg b.i.d. 13 0.56 (0.49 to 0.63) 0.51 (0.46 to 0.58) 0.51 (0.45 to 0.57) Sildenafil 100 mg (single dose) administered alone 25 mg (single dose) when administered with darunavir/ ritonavir 400/100 mg b.i.d. 16 0.62 (0.55 to 0.70) 0.97 (0.86 to 1.09) S-warfarin 7-OH-S-warfarin 10 mg single dose 600/100 mg b.i.d. 12 12 0.92 (0.86 to 0.97) 1.42 (1.24 to 1.63) 0.79 (0.73 to 0.85) 1.23 (0.97 to 1.57) - 12.4 Microbiology. Mechanism of ActionDarunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.Antiviral ActivityDarunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against broad panel of HIV-1 group (A, B, C, D, E, F, G), and group primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.ResistanceCell Culture: HIV-1 isolates with decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed to of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.Clinical Trials Of Darunavir/Ritonavir In Treatment-Experienced Subjects: In pooled analysis of the 600/100 mg darunavir/ritonavir twice daily arms of trials TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine trials TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or developed most frequently on darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in darunavir/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some darunavir/ritonavir virologic failure isolates. In trial TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on darunavir/ritonavir.In the 96-week as-treated analysis of the Phase trial TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving darunavir/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.In the 48-week analysis of the Phase trial TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on darunavir/ritonavir 800/100 mg once daily and had post- baseline genotypes showed that subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to subjects (5/39; 13%) on darunavir/ritonavir 600/100 mg twice daily. Isolates from subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; subject isolate in the darunavir/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with 24-fold decreased susceptibility to darunavir, and subject isolate in the darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with 40-fold decreased susceptibility to darunavir. In the darunavir/ritonavir 800/100 mg once daily and darunavir/ritonavir 600/100 mg twice daily groups, isolates from (7/60; 12%) and (4/42; 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.Clinical Trials Of Darunavir/Ritonavir In Treatment-Naive Subjects: In the 192-week as-treated analysis censoring those who discontinued before Week of the Phase trial TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the darunavir/ritonavir arm, emergent PI resistance- associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in virologic failures from the darunavir/ritonavir arm and virologic failures in the lopinavir/ritonavir arm.Cross-resistanceCross-resistance among PIs has been observed. Darunavir has less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed fold change in EC50 values less than for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In trials TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily (greater than 7-fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).In trial TMC114-C214, the darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos) amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these were resistant to saquinavir and were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.Baseline Genotype/Phenotype and Virologic Outcome AnalysesGenotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of darunavir/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as- treated analyses using pooled data from the Phase 2b trials (Trials TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine trials TMC125-C206 and TMC125-C216 at Week 24 (n=591).Diminished virologic responses were observed in subjects with or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 17). Table 17: Response to Darunavir/ritonavir 600/100 mg Twice Daily by Baseline Number of IAS-Defined Primary PI Resistance-Associated Substitutions: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215 ENF=enfuvirtide IAS-defined primary PI substitutions Proportion of subjects with <50 copies/mL at Week 96 N=439 Overallde novo ENF Re-used/No ENF All 44% (192/439) 54% (61/112) 40% (131/327) to 50% (162/322) 58% (49/85) 48% (113/237) 22% (16/74) 47% (9/19) 13% (7/55) >=6 9% (3/32) 17% (1/6) 8% (2/26) IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90MThe presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with decreased virologic response to darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, and greater than or equal to of these substitutions, respectively.Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 18. These baseline phenotype groups are based on the select patient populations in the trials TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for darunavir/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir. Table 18: Response (HIV-1 RNA <50 copies/mL at Week 96) to Darunavir/ritonavir 600/100 mg Twice Daily by Baseline Darunavir Phenotype and by Use of Enfuvirtide: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215 ENF=enfuvirtide Baseline DRV phenotype Proportion of subjects with <50 copies/mL at Week 96 N=417 Allde novo ENF Re-used/No ENF Overall 175/417 (42%) 61/112 (54%) 131/327 (40%) to 148/270 (55%) 44/65 (68%) 104/205 (51%) >7 to 20 16/53 (30%) 7/17 (41%) 9/36 (25%) >20 11/94 (12%) 6/23 (26%) 5/71 (7%) chart 1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Darunavir tablets, co-administered with ritonavir (darunavir/ritonavir), in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adult and pediatric patients years of age and older [see Use in Specific Populations (8.4) and Clinical Studies (14)].. Darunavir is human immunodeficiency virus (HIV-1) protease inhibitor indicated for the treatment of HIV-1 infection in adult and pediatric patients years of age and older. Darunavir tablets must be co-administered with ritonavir (darunavir/ritonavir) and with other antiretroviral agents. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instruction for Use).Instructions for UseAdvise patients to take darunavir and ritonavir with food every day on regular dosing schedule, as missed doses can result in development of resistance. Darunavir tablets must always be used with ritonavir in combination with other antiretroviral drugs. Advise patients not to alter the dose of either darunavir or ritonavir, discontinue ritonavir, or discontinue therapy with darunavir tablets without consulting their physician [see Dosage and Administration (2)].HepatotoxicityInform patients that drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir co-administered with 100 mg of ritonavir. Advise patients about the signs and symptoms of liver problems [see Warnings and Precautions (5.2)].Severe Skin ReactionsInform patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, have been reported with darunavir co-administered with 100 mg of ritonavir. Advise patients to discontinue darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia [see Warnings and Precautions (5.3)].Drug InteractionsDarunavir/ritonavir may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johns wort [see Contraindications (4), Warnings and Precautions (5.4, 5.5) and Drug Interactions (7)].ContraceptionInstruct patients receiving combined hormonal contraception or the progestin only pill to use an effective alternative (non-hormonal) contraceptive method or add barrier method during therapy with darunavir/ritonavir because hormonal levels may decrease [see Drug Interactions (7.3) and Use in Specific Populations (8.3)].Fat RedistributionInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including darunavir/ritonavir, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)].Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.8)]. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to darunavir [see Use in Specific Populations (8.1)].LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].All brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.Manufactured for:Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United States.Manufactured by:Lupin LimitedNagpur 441 108INDIA.Revised: January 2024.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of labeling:Hepatotoxicity [see Warnings and Precautions (5.2)] Severe Skin Reactions [see Warnings and Precautions (5.3)] Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6)] Fat Redistribution [see Warnings and Precautions (5.7)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8)] Hemophilia [see Warnings and Precautions (5.9)] Due to the need for co-administration of darunavir with ritonavir, please refer to ritonavir prescribing information for ritonavir-associated adverse reactions.. Hepatotoxicity [see Warnings and Precautions (5.2)] Severe Skin Reactions [see Warnings and Precautions (5.3)] Diabetes Mellitus/Hyperglycemia [see Warnings and Precautions (5.6)] Fat Redistribution [see Warnings and Precautions (5.7)] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8)] Hemophilia [see Warnings and Precautions (5.9)] The most common clinical adverse drug reactions to darunavir/ritonavir (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. (6)To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common clinical adverse drug reactions to darunavir/ritonavir (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. (6). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Treatment Naive-Adults:TMC114-C211The safety assessment is based on all safety data from the Phase trial TMC114-C211 comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day in 689 antiretroviral treatment-naive HIV-1-infected adult subjects. The total mean exposure for subjects in the darunavir/ritonavir 800/100 mg once daily arm and in the lopinavir/ritonavir 800/200 mg per day arm was 162.5 and 153.5 weeks, respectively.The majority of the adverse drug reactions (ADRs) reported during treatment with darunavir/ritonavir 800/100 mg once daily were mild in severity. The most common clinical ADRs to darunavir/ritonavir 800/100 mg once daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, headache, abdominal pain and rash. 2.3% of subjects in the darunavir/ritonavir arm discontinued treatment due to ADRs.ADRs to darunavir/ritonavir 800/100 mg once daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-naive HIV-1-infected adult subjects are presented in Table and subsequent text below the table. Table 6: Selected Clinical Adverse Drug Reactions to Darunavir/Ritonavir 800/100 mg Once Dailya of at Least Moderate Intensity (>=Grade 2) Occurring in >=2% of Antiretroviral Treatment-Naive HIV-1-Infected Adult Subjects (Trial TMC114-C211) N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarateaExcluding laboratory abnormalities reported as ADRs. System organ class, preferred term, Darunavir/Ritonavir 800/100 mg once daily TDF/FTC N=343 Lopinavir/Ritonavir 800/200 mg per day +TDF/FTC N=346 Gastrointestinal Disorders Abdominal pain 6% 6% Diarrhea 9% 16% Nausea 4% 4% Vomiting 2% 4% General Disorders and Administration Site Conditions Fatigue <1% 3% Metabolism and Nutrition Disorders Anorexia 2% <1% Nervous System Disorders Headache 7% 6% Skin and Subcutaneous Tissue Disorders Rash 6% 7% Less Common Adverse ReactionsTreatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-naive subjects receiving darunavir/ritonavir 800/100 mg once daily are listed below by body system:Gastrointestinal Disorders: acute pancreatitis, dyspepsia, flatulenceGeneral Disorders and Administration Site Conditions: astheniaHepatobiliary Disorders: acute hepatitis (e.g., acute hepatitis, cytolytic hepatitis, hepatotoxicity)Immune System Disorders: (drug) hypersensitivity, immune reconstitution syndromeMetabolism and Nutrition Disorders: diabetes mellitusMusculoskeletal and Connective Tissue Disorders: myalgia, osteonecrosisPsychiatric Disorders: abnormal dreamsSkin and Subcutaneous Tissue Disorders: angioedema, pruritus, Stevens-Johnson Syndrome, urticariaLaboratory Abnormalities:Selected Grade to laboratory abnormalities that represent worsening from baseline observed in antiretroviral treatment-naive adult subjects treated with darunavir/ritonavir 800/100 mg once daily are presented in Table 7. Table 7: Grade to Laboratory Abnormalities Observed in Antiretroviral Treatment-Naive HIV-1 Infected Adult Subjectsa (Trial TMC114-C211) N=total number of subjects per treatment group; FTC=emtricitabine; TDF=tenofovir disoproxil fumarate aGrade data not applicable in Division of AIDS grading scale. Laboratory parameter Limit Darunavir/Ritonavir 800/100 mg once daily TDF/FTC Lopinavir/Ritonavir 800/200 mg per day TDF/FTC Biochemistry Alanine Aminotransferase Grade >2.5 to <=5.0 ULN 9% 9% Grade >5.0 to <=10.0 ULN 3% 3% Grade >10.0 ULN <1% 3% Aspartate Aminotransferase Grade >2.5 to <=5.0 ULN 7% 10% Grade >5.0 to <=10.0 ULN 4% 2% Grade >10.0 ULN 1% 3% Alkaline Phosphatase Grade >2.5 to <=5.0 ULN 1% 1% Grade >5.0 to <=10.0 ULN 0% <1% Grade >10.0 ULN 0% 0% Hyperbilirubinemia Grade >1.5 to <=2.5 ULN <1% 5% Grade >2.5 to <=5.0 ULN <1% <1% Grade >5.0 ULN 0% 0% Triglycerides Grade 5.65 to 8.48 mmol/L 500 to 750 mg/dL 3% 10% Grade 8.49 to 13.56 mmol/L 751 to 1200 mg/dL 2% 5% Grade >13.56 mmol/L >1200 mg/dL 1% 1% Total Cholesterol Grade 6.20 to 7.77 mmol/L 240 to 300 mg/dL 23% 27% Grade >7.77 mmol/L >300 mg/dL 1% 5% Low-Density Lipoprotein Cholesterol Grade 4.13 to 4.90 mmol/L 160 to 190 mg/dL 14% 12% Grade >=4.91 mmol/L >=191 mg/dL 9% 6% Elevated Glucose Levels Grade 6.95 to 13.88 mmol/L 126 to 250 mg/dL 11% 10% Grade 13.89 to 27.75 mmol/L 251 to 500 mg/dL 1% <1% Grade >27.75 mmol/L >500 mg/dL 0% 0% Pancreatic Lipase Grade >1.5 to <=3.0 ULN 3% 2% Grade >3.0 to <=5.0 ULN <1% 1% Grade >5.0 ULN 0% <1% Pancreatic Amylase Grade >1.5 to <=2.0 ULN 5% 2% Grade >2.0 to <=5.0 ULN 5% 4% Grade >5.0 ULN 0% <1% Treatment-Experienced Adults: TMC114-C214The safety assessment is based on all safety data from the Phase trial TMC114-C214 comparing darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in 595 antiretroviral treatment-experienced HIV-1-infected adult subjects. The total mean exposure for subjects in the darunavir/ritonavir 600/100 mg twice daily arm and in the lopinavir/ritonavir 400/100 mg twice daily arm was 80.7 and 76.4 weeks, respectively.The majority of the ADRs reported during treatment with darunavir/ritonavir 600/100 mg twice daily were mild in severity. The most common clinical ADRs to darunavir/ritonavir 600/100 mg twice daily (greater than or equal to 5%) of at least moderate intensity (greater than or equal to Grade 2) were diarrhea, nausea, rash, abdominal pain and vomiting. 4.7% of subjects in the darunavir/ritonavir arm discontinued treatment due to ADRs.ADRs to darunavir/ritonavir 600/100 mg twice daily of at least moderate intensity (greater than or equal to Grade 2) in antiretroviral treatment-experienced HIV-1-infected adult subjects are presented in Table and subsequent text below the table. Table 8: Selected Clinical Adverse Drug Reactions to Darunavir/Ritonavir 600/100 mg Twice Dailya of at Least Moderate Intensity (>=Grade 2) Occurring in >=2% of Antiretroviral Treatment- Experienced HIV-1-Infected Adult Subjects (Trial TMC114-C214) N=total number of subjects per treatment group; OBR=optimized background regimenaExcluding laboratory abnormalities reported as ADRs System organ class, preferred term, Darunavir/Ritonavir 600/100 mg twice daily OBR N=298 Lopinavir/Ritonavir 400/100 mg twice daily OBR N=297 Gastrointestinal Disorders Abdominal distension 2% <1% Abdominal pain 6% 3% Diarrhea 14% 20% Dyspepsia 2% 1% Nausea 7% 6% Vomiting 5% 3% General Disorders and Administration Site Conditions Asthenia 3% 1% Fatigue 2% 1% Metabolism and Nutrition Disorders Anorexia 2% 2% Diabetes mellitus 2% <1% Nervous System Disorders Headache 3% 3% Skin and Subcutaneous Tissue Disorders Rash 7% 3% Less Common Adverse Reactions:Treatment-emergent ADRs of at least moderate intensity (greater than or equal to Grade 2) occurring in less than 2% of antiretroviral treatment-experienced subjects receiving darunavir/ritonavir 600/100 mg twice daily are listed below by body system:Gastrointestinal Disorders: acute pancreatitis, flatulence Musculoskeletal and Connective Tissue Disorders: myalgia Psychiatric Disorders: abnormal dreamsSkin and Subcutaneous Tissue Disorders: pruritus, urticariaLaboratory Abnormalities:Selected Grade to laboratory abnormalities that represent worsening from baseline observed in antiretroviral treatment-experienced adult subjects treated with darunavir/ritonavir 600/100 mg twice daily are presented in Table 9. Table 9: Grade to Laboratory Abnormalities Observed in Antiretroviral Treatment-Experienced HIV-1-Infected Adult Subjectsa (Trial TMC114-C214) N=total number of subjects per treatment group; OBR=optimized background regimenaGrade data not applicable in Division of AIDS grading scale Laboratory parameter, Limit Darunavir/Ritonavir 600/100 mg twice daily OBR Lopinavir/Ritonavir 400/100 mg twice daily OBR Biochemistry Alanine Aminotransferase Grade >2.5 to <=5.0 ULN 7% 5% Grade >5.0 to <=10.0 ULN 2% 2% Grade >10.0 ULN 1% 2% Aspartate Aminotransferase Grade >2.5 to <=5.0 ULN 6% 6% Grade >5.0 to <=10.0 ULN 2% 2% Grade >10.0 ULN <1% 2% Alkaline Phosphatase Grade >2.5 to <=5.0 ULN <1% 0% Grade >5.0 to <=10.0 ULN <1% <1% Grade >10.0 ULN 0% 0% Hyperbilirubinemia Grade >1.5 to <=2.5 ULN <1% 2% Grade >2.5 to <=5.0 ULN <1% <1% Grade >5.0 ULN <1% 0% Triglycerides Grade 5.65 to 8.48 mmol/L 500 to 750 mg/dL 10% 11% Grade 8.49 to 13.56 mmol/L 751 to 1200 mg/dL 7% 10% Grade >13.56 mmol/L >1200 mg/dL 3% 6% Total Cholesterol Grade 6.20 to 7.77 mmol/L 240 to 300 mg/dL 25% 23% Grade >7.77 mmol/L >300 mg/dL 10% 14% Low-Density Lipoprotein Cholesterol Grade 4.13 to 4.90 mmol/L 160 to 190 mg/dL 14% 14% Grade >=4.91 mmol/L >=191 mg/dL 8% 9% Elevated Glucose Levels Grade 6.95 to 13.88 mmol/L 126 to 250 mg/dL 10% 11% Grade 13.89 to 27.75 mmol/L 251 to 500 mg/dL 1% <1% Grade >27.75 mmol/L >500 mg/dL <1% 0% Pancreatic Lipase Grade >1.5 to <=3.0 ULN 3% 4% Grade >3.0 to <=5.0 ULN 2% <1% Grade >5.0 ULN <1% 0% Pancreatic Amylase Grade >1.5 to <=2.0 ULN 6% 7% Grade >2.0 to <=5.0 ULN 7% 3% Grade >5.0 ULN 0% 0% Serious ADRsThe following serious ADRs of at least moderate intensity (greater than or equal to Grade 2) occurred in the Phase 2b and Phase trials with darunavir/ritonavir: abdominal pain, acute hepatitis, acute pancreatitis, anorexia, asthenia, diabetes mellitus, diarrhea, fatigue, headache, hepatic enzyme increased, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, immune reconstitution syndrome, low density lipoprotein increased, nausea, pancreatic enzyme increased, rash, Stevens-Johnson Syndrome, and vomiting.Patients Co-Infected with Hepatitis and/or Hepatitis VirusIn subjects co-infected with hepatitis or virus receiving darunavir/ritonavir, the incidence of adverse events and clinical chemistry abnormalities was not higher than in subjects receiving darunavir/ritonavir who were not co-infected, except for increased hepatic enzymes [see Warnings and Precautions (5.2)]. The pharmacokinetic exposure in co-infected subjects was comparable to that in subjects without co-infection.Clinical Trials Experience: Pediatric PatientsDarunavir/ritonavir has been studied in combination with other antiretroviral agents in Phase trials. TMC114-C212, in which 80 antiretroviral treatment-experienced HIV-1 infected pediatric subjects to less than 18 years of age and weighing at least 20 kg were included, TMC114-C228, in which 21 antiretroviral treatment-experienced HIV-1-infected pediatric subjects to less than years of age and weighing at least 10 kg were included, and TMC114-C230 in which 12 antiretroviral treatment-naive HIV-1 infected pediatric patients aged from 12 to less than 18 years and weighing at least 40 kg were included. The TMC114-C212 and C228 trials evaluated darunavir/ritonavir twice daily dosing and the TMC114-C230 trial evaluated darunavir/ritonavir once daily dosing [see Use in Specific Populations (8.4) and Clinical Studies (14.4)].Frequency, type, and severity of ADRs in pediatric subjects were comparable to those observed in adults.TMC114-C212Clinical ADRs to darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (13%), diarrhea (11%), abdominal pain (10%), headache (9%), rash (5%), nausea (4%), and fatigue (3%).Grade or laboratory abnormalities were ALT increased (Grade 3: 3%; Grade 4: 1%), AST increased (Grade 3: 1%), pancreatic amylase increased (Grade 3: 4%, Grade 4: 1%), pancreatic lipase increased (Grade 3: 1%), total cholesterol increased (Grade 3: 1%), and LDL increased (Grade 3: 3%).TMC114-C228Clinical ADRs to darunavir/ritonavir (all grades, greater than or equal to 5%), were diarrhea (24%), vomiting (19%), rash (19%), abdominal pain (5%), and anorexia (5%). There were no Grade or laboratory abnormalities considered as ADRs in this trial.TMC114-C230Clinical ADRs to darunavir/ritonavir (all grades, greater than or equal to 3%), were vomiting (33%), nausea (25%), diarrhea (16.7%), abdominal pain (8.3%), decreased appetite (8.3%), pruritus (8.3%), and rash (8.3%).There were no Grade or laboratory abnormalities considered as ADRs in this trial.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of darunavir. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Metabolism and Nutrition DisordersRedistribution of body fatMusculoskeletal and Connective Tissue DisordersRhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and darunavir/ritonavir)Skin and Subcutaneous Tissue DisordersToxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3)]Renal and Urinary DisordersCrystal nephropathy, crystalluria.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Darunavir is an HIV-1 antiviral drug [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionDarunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV-1 encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.Antiviral ActivityDarunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in cell culture against broad panel of HIV-1 group (A, B, C, D, E, F, G), and group primary isolates with EC50 values ranging from less than 0.1 to 4.3 nM. The EC50 value of darunavir increases by median factor of 5.4 in the presence of human serum. Darunavir did not show antagonism when studied in combination with the PIs amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, the NNRTIs delavirdine, rilpivirine, efavirenz, etravirine, or nevirapine, and the fusion inhibitor enfuvirtide.ResistanceCell Culture: HIV-1 isolates with decreased susceptibility to darunavir have been selected in cell culture and obtained from subjects treated with darunavir/ritonavir. Darunavir-resistant virus derived in cell culture from wild-type HIV-1 had 21- to 88-fold decreased susceptibility to darunavir and developed to of the following amino acid substitutions S37D, R41E/T, K55Q, H69Q, K70E, T74S, V77I, or I85V in the protease. Selection in cell culture of darunavir resistant HIV-1 from nine HIV-1 strains harboring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease gene, coding for amino acid substitutions L10F, V11I, I13V, I15V, G16E, L23I, V32I, L33F, S37N, M46I, I47V, I50V, F53L, L63P, A71V, G73S, L76V, V82I, I84V, T91A/S, and Q92R, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were the most prevalent. These darunavir-resistant viruses had at least eight protease substitutions and exhibited 50- to 641-fold decreases in darunavir susceptibility with final EC50 values ranging from 125 nM to 3461 nM.Clinical Trials Of Darunavir/Ritonavir In Treatment-Experienced Subjects: In pooled analysis of the 600/100 mg darunavir/ritonavir twice daily arms of trials TMC114-C213, TMC114-C202, TMC114-C215, and the control arms of etravirine trials TMC125-C206 and TMC125-C216, the amino acid substitutions V32I and I54L or developed most frequently on darunavir/ritonavir in 41% and 25%, respectively, of the treatment-experienced subjects who experienced virologic failure, either by rebound or by never being suppressed (less than 50 copies/mL). Other substitutions that developed frequently in darunavir/ritonavir virologic failure isolates occurred at amino acid positions V11I, I15V, L33F, I47V, I50V, and L89V. These amino acid substitutions were associated with decreased susceptibility to darunavir; 90% of the virologic failure isolates had greater than 7-fold decrease in susceptibility to darunavir at failure. The median darunavir phenotype (fold change from reference) of the virologic failure isolates was 4.3-fold at baseline and 85-fold at failure. Amino acid substitutions were also observed in the protease cleavage sites in the Gag polyprotein of some darunavir/ritonavir virologic failure isolates. In trial TMC114-C212 of treatment-experienced pediatric subjects, the amino acid substitutions V32I, I54L and L89M developed most frequently in virologic failures on darunavir/ritonavir.In the 96-week as-treated analysis of the Phase trial TMC114-C214, the percent of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 21% (62/298) in the group of subjects receiving darunavir/ritonavir 600/100 mg twice daily compared to 32% (96/297) of subjects receiving lopinavir/ritonavir 400/100 mg twice daily. Examination of subjects who failed on darunavir/ritonavir 600/100 mg twice daily and had post-baseline genotypes and phenotypes showed that subjects (7/43; 16%) developed PI substitutions on darunavir/ritonavir treatment resulting in decreased susceptibility to darunavir. Six of the had baseline PI resistance-associated substitutions and baseline darunavir phenotypes greater than 7. The most common emerging PI substitutions in these virologic failures were V32I, L33F, M46I or L, I47V, I54L, T74P and L76V. These amino acid substitutions were associated with 59- to 839-fold decreased susceptibility to darunavir at failure. Examination of individual subjects who failed in the comparator arm on lopinavir/ritonavir and had post-baseline genotypes and phenotypes showed that 31 subjects (31/75; 41%) developed substitutions on lopinavir treatment resulting in decreased susceptibility to lopinavir (greater than 10-fold) and the most common substitutions emerging on treatment were L10I or F, M46I or L, I47V or A, I54V and L76V. Of the 31 lopinavir/ritonavir virologic failure subjects, 14 had reduced susceptibility (greater than 10-fold) to lopinavir at baseline.In the 48-week analysis of the Phase trial TMC114-C229, the number of virologic failures (including those who discontinued before suppression after Week 4) was 26% (75/294) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 19% (56/296) of subjects receiving darunavir/ritonavir 600/100 mg twice daily. Examination of isolates from subjects who failed on darunavir/ritonavir 800/100 mg once daily and had post- baseline genotypes showed that subjects (8/60; 13%) had isolates that developed IAS-USA defined PI resistance-associated substitutions compared to subjects (5/39; 13%) on darunavir/ritonavir 600/100 mg twice daily. Isolates from subjects developed PI resistance associated substitutions associated with decreased susceptibility to darunavir; subject isolate in the darunavir/ritonavir 800/100 mg once daily arm, developed substitutions V32I, M46I, L76V and I84V associated with 24-fold decreased susceptibility to darunavir, and subject isolate in the darunavir/ritonavir 600/100 mg twice daily arm developed substitutions L33F and I50V associated with 40-fold decreased susceptibility to darunavir. In the darunavir/ritonavir 800/100 mg once daily and darunavir/ritonavir 600/100 mg twice daily groups, isolates from (7/60; 12%) and (4/42; 10%) virologic failures, respectively, developed decreased susceptibility to an NRTI included in the treatment regimen.Clinical Trials Of Darunavir/Ritonavir In Treatment-Naive Subjects: In the 192-week as-treated analysis censoring those who discontinued before Week of the Phase trial TMC114-C211, the percentage of virologic failures (never suppressed, rebounders and discontinued before achieving suppression) was 22% (64/288) in the group of subjects receiving darunavir/ritonavir 800/100 mg once daily compared to 29% (76/263) of subjects receiving lopinavir/ritonavir 800/200 mg per day. In the darunavir/ritonavir arm, emergent PI resistance- associated substitutions were identified in 11 of the virologic failures with post-baseline genotypic data (n=43). However, none of the darunavir virologic failures had decrease in darunavir susceptibility (greater than 7-fold change) at failure. In the comparator lopinavir/ritonavir arm, emergent PI resistance-associated substitutions were identified in 17 of the virologic failures with post-baseline genotypic data (n=53), but none of the lopinavir/ritonavir virologic failures had decreased susceptibility to lopinavir (greater than 10-fold change) at failure. The reverse transcriptase M184V substitution and/or resistance to emtricitabine, which was included in the fixed background regimen, was identified in virologic failures from the darunavir/ritonavir arm and virologic failures in the lopinavir/ritonavir arm.Cross-resistanceCross-resistance among PIs has been observed. Darunavir has less than 10-fold decreased susceptibility in cell culture against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to these PIs remain susceptible to darunavir.Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir or saquinavir in cell culture. However, six of nine darunavir-resistant viruses selected in cell culture from PI-resistant viruses showed fold change in EC50 values less than for tipranavir, indicative of limited cross-resistance between darunavir and tipranavir. In trials TMC114-C213, TMC114-C202, and TMC114-C215, 34% (64/187) of subjects in the darunavir/ritonavir arm whose baseline isolates had decreased susceptibility to tipranavir (tipranavir fold change greater than 3) achieved less than 50 copies/mL serum HIV-1 RNA levels at Week 96. Of the viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily (greater than 7-fold change), 41% were still susceptible to tipranavir and 10% were susceptible to saquinavir while less than 2% were susceptible to the other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir or nelfinavir).In trial TMC114-C214, the darunavir/ritonavir virologic failures with reduced susceptibility to darunavir at failure were also resistant to the approved PIs (fos) amprenavir, atazanavir, lopinavir, indinavir, and nelfinavir at failure. Six of these were resistant to saquinavir and were resistant to tipranavir. Four of these virologic failures were already PI-resistant at baseline.Cross-resistance between darunavir and nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, or integrase inhibitors is unlikely because the viral targets are different.Baseline Genotype/Phenotype and Virologic Outcome AnalysesGenotypic and/or phenotypic analysis of baseline virus may aid in determining darunavir susceptibility before initiation of darunavir/ritonavir 600/100 mg twice daily therapy. The effect of baseline genotype and phenotype on virologic response at 96 weeks was analyzed in as- treated analyses using pooled data from the Phase 2b trials (Trials TMC114-C213, TMC114-C202, and TMC114-C215) (n=439). The findings were confirmed with additional genotypic and phenotypic data from the control arms of etravirine trials TMC125-C206 and TMC125-C216 at Week 24 (n=591).Diminished virologic responses were observed in subjects with or more baseline IAS-defined primary protease inhibitor resistance-associated substitutions (D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M) (see Table 17). Table 17: Response to Darunavir/ritonavir 600/100 mg Twice Daily by Baseline Number of IAS-Defined Primary PI Resistance-Associated Substitutions: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215 ENF=enfuvirtide IAS-defined primary PI substitutions Proportion of subjects with <50 copies/mL at Week 96 N=439 Overallde novo ENF Re-used/No ENF All 44% (192/439) 54% (61/112) 40% (131/327) to 50% (162/322) 58% (49/85) 48% (113/237) 22% (16/74) 47% (9/19) 13% (7/55) >=6 9% (3/32) 17% (1/6) 8% (2/26) IAS Primary PI Substitutions (2008): D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90MThe presence at baseline of two or more of the substitutions V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V or L89V was associated with decreased virologic response to darunavir/ritonavir. In subjects not taking enfuvirtide de novo, the proportion of subjects achieving viral load less than 50 plasma HIV-1 RNA copies/mL at 96 weeks was 59%, 29%, and 12% when the baseline genotype had 0-1, and greater than or equal to of these substitutions, respectively.Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 18. These baseline phenotype groups are based on the select patient populations in the trials TMC114-C213, TMC114-C202, and TMC114-C215, and are not meant to represent definitive clinical susceptibility breakpoints for darunavir/ritonavir. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir. Table 18: Response (HIV-1 RNA <50 copies/mL at Week 96) to Darunavir/ritonavir 600/100 mg Twice Daily by Baseline Darunavir Phenotype and by Use of Enfuvirtide: As-treated Analysis of Trials TMC114-C213, TMC114-C202, and TMC114-C215 ENF=enfuvirtide Baseline DRV phenotype Proportion of subjects with <50 copies/mL at Week 96 N=417 Allde novo ENF Re-used/No ENF Overall 175/417 (42%) 61/112 (54%) 131/327 (40%) to 148/270 (55%) 44/65 (68%) 104/205 (51%) >7 to 20 16/53 (30%) 7/17 (41%) 9/36 (25%) >20 11/94 (12%) 6/23 (26%) 5/71 (7%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisDarunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).Darunavir was not mutagenic or genotoxic in battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.Impairment of FertilityNo effects on fertility or early embryonic development were observed with darunavir in rats.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Description of Adult Clinical Trials. The evidence of efficacy of darunavir/ritonavir is based on the analyses of 192-week data from randomized, controlled open-label Phase trial in treatment-naive (TMC114-C211) HIV-1-infected adult subjects and 96-week data from randomized, controlled, open-label Phase trial in antiretroviral treatment-experienced (TMC114-C214) HIV-1-infected adult subjects. In addition, 96-week data are included from randomized, controlled Phase 2b trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1-infected adult subjects.. 14.2 Treatment-Naive Adult Subjects. TMC114-C211TMC114-C211 is randomized, controlled, open-label Phase trial comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir 800/200 mg per day (given as twice daily or as once daily regimen) in antiretroviral treatment-naive HIV-1-infected adult subjects. Both arms used fixed background regimen consisting of tenofovir disoproxil fumarate 300 mg once daily (TDF) and emtricitabine 200 mg once daily (FTC).HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than or equal to 5000 copies/mL. Randomization was stratified by screening plasma viral load (HIV-1 RNA less than 100,000 copies/mL or greater than or equal to 100,000 copies/mL) and screening CD4+ cell count (less than 200 cells/mm3 or greater than or equal to 200 cells/mm3). Virologic response was defined as confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 689 subjects in trial TMC114-C211 who had completed 192 weeks of treatment or discontinued earlier.Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 19). Table 19 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 800/100 mg once daily arm and subjects in the lopinavir/ritonavir 800/200 mg per day arm in trial TMC114-C211. Table 19: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C211 FTC=emtricitabine; TDF=tenofovir disoproxil fumarate Darunavir/ritonavir 800/100 mg Once Daily TDF/FTC N=343 Lopinavir/ritonavir 800/200 mg Per Day TDF/FTC N=346 Demographic characteristics Median age (years) (range, years) 34 (18 to 70) 33 (19 to 68) Sex Male 70% 70% Female 30% 30% Race White 40% 45% Black 23% 21% Hispanic 23% 22% Asian 13% 11% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.86 4.84 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 228 (4 to 750) 218 (2 to 714) Percentage of patients with baseline viral load >=100,000 copies/mL 34% 35% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 41% 43% Week 192 outcomes for subjects on darunavir/ritonavir 800/100 mg once daily from trial TMC114-C211 are shown in Table 20. Table 20: Virologic Outcome of Randomized Treatment of Trial TMC114-C211 at 192 Weeks = total number of subjects with data; FTC emtricitabine; TDF tenofovir disoproxil fumaratea95% CI: 1.9; 16.1 bIncludes patients who discontinued prior to Week 192 for lack or loss of efficacy and patients who are >=50 copies in the 192-week window and patients who had change in their background regimen that was not permitted by the protocol.cWindow 186 to 198 Weeks.dIncludes patients who discontinued due to adverse event or death at any time point from Day through the time window if this resulted in no virologic data on treatment during the specified window.eOther includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL Darunavir/ritonavir 800/100 mg Once Daily TDF/FTC N=343 Lopinavir/ritonavir 800/200 mg Per Day TDF/FTC N=346 Virologic success HIV-1 RNA <50 copies/mL 70%a 61% Virologic failureb 12% 15% No virologic data at Week 192 windowc Reasons Discontinued trial due to adverse event or deathd 5% 13% Discontinued trial for other reasonse 13% 12% Missing data during windowc but on trial <1% 0% In trial TMC114-C211 at 192 weeks of treatment, the median increase from baseline in CD4+ cell counts was 258 cells/mm3 in the darunavir/ritonavir 800/100 mg once daily arm and 263 cells/mm3 in the lopinavir/ritonavir 800/200 mg per day arm. Of the darunavir/ritonavir subjects with confirmed virologic response of <50 copies/mL at Week 48, 81% remained undetectable at Week 192 versus 68% with lopinavir/ritonavir. In the 192 week analysis, statistical superiority of the darunavir/ritonavir regimen over the lopinavir/ritonavir regimen was demonstrated for both ITT and OP populations.. 14.3 Treatment-Experienced Adult Subjects. TMC114-C229TMC114-C229 is randomized, open-label trial comparing darunavir/ritonavir 800/100 mg once daily to darunavir/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1 infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to NRTIs selected by the investigator.HIV-1-infected subjects who were eligible for this trial were on highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.Table 21 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 800/100 mg once daily arm and subjects in the darunavir/ritonavir 600/100 mg twice daily arm in trial TMC114-C229. No imbalances between the arms were noted. Table 21: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C229 OBR=optimized background regimena Based on phenotype (Antivirogram(R))b Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med 2008; 16(5): 138-145c Only counting ARVs, excluding low-dose ritonavir Darunavir/Ritonavir 800/100 mg Once Daily OBR N=294 Darunavir/Ritonavir 600/100 mg Twice Daily OBR N=296 Demographic characteristics Median age (years) (range, years) 40 (18 to 70) 40 (18 to 77) Sex Male 61% 67% Female 39% 33% Race White 35% 37% Black 28% 24% Hispanic 16% 20% Asian 16% 14% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.19 4.13 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 219 (24 to 1306) 236 (44 to 864) Percentage of patients with baseline viral load >=100,000 copies/mL 13% 11% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 43% 39% Median darunavir fold change (range)a 0.50 (0.1 to 1.8) 0.50 (0.1 to 1.9) Median number of resistance-associatedb: PI mutations 4 NNRTI mutations 1 NRTI mutations 1 Percentage of subjects susceptible to all available PIs at baseline 88% 86% Percentage of subjects with number of baseline primary protease inhibitor mutationsb: 84% 84% 8% 9% 5% 4% >=3 3% 2% Median number of ARVs previously usedc: NRTIs 3 NNRTIs 1 PIs (excluding low-dose ritonavir) 1 Week 48 outcomes for subjects on darunavir/ritonavir 800/100 mg once daily from trial TMC114-C229 are shown in Table 22. Table 22: Virologic Outcome of Randomized Treatment of Trial TMC114-C229 at 48 Weeks = total number of subjects with data; OBR=optimized background regimena Includes patients who discontinued prior to Week 48 for lack or loss of efficacy, patients who are >=50 copies in the 48-week window, patients who had change in their background regimen that was not permitted in the protocol (provided the switch occurred before the earliest onset of an AE leading to permanent stop of trial medication) and patients who discontinued for reasons other than AEs/death and lack or loss of efficacy (provided their last available viral load was detectable (HIV RNA >=50 copies/mL).b Window 42 to 54 Weeksc Patients who discontinued due to adverse event or death at any time point from Day through the time window if this resulted in no virologic data on treatment during the specified window.d Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL. Darunavir/Ritonavir 800/100 mg once daily OBR N=294 Darunavir/Ritonavir 600/100 mg twice daily OBR N=296 Virologic success HIV-1 RNA <50 copies/mL 69% 69% Virologic failurea 26% 23% No virologic data at Week 48 windowb Reasons Discontinued trial due to adverse event or deathc 3% 4% Discontinued trial for other reasonsd 2% 3% Missing data during windowb but on trial 0% <1% The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the darunavir/ritonavir 800/100 mg once daily arm and the darunavir/ritonavir 600/100 mg twice daily arm, respectively).TMC114-C214TMC114-C214 is randomized, controlled, open-label Phase trial comparing darunavir/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naive HIV-1-infected adult subjects. Both arms used an optimized background regimen consisting of at least antiretrovirals (NRTIs with or without NNRTIs).HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in trial TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.Demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the lopinavir/ritonavir arm (see Table 23). Table 23 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in trial TMC114-C214. Table 23: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C214 OBR=optimized background regimena Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125-130b Only counting ARVs, excluding low-dose ritonavirc Based on phenotype (Antivirogram(R))d Commercially available PIs at the time of trial enrollment Darunavir/Ritonavir 600/100 mg Twice Daily OBR N=298 Darunavir/Ritonavir 400/100 mg Twice Daily OBR N=297 Demographic characteristics Median age (years) (range, years) 40 (18 to 68) 41 (22 to 76) Sex Male 77% 81% Female 23% 19% Race White 54% 57% Black 18% 17% Hispanic 15% 15% Asian 9% 9% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.33 4.28 Median baseline CD4+ cell count (cells/mm3) (range,cells/mm3) 235 (3 to 831) 230 (2 to 1096) Percentage of patients with baseline viral load 19% 17% >=100,000 copies/mL Percentage of patients with baseline CD4+ cell count <200 cells/mm3 40% 40% Median darunavir fold change (range) 0.60 (0.10 to 37.40) 0.60 (0.1 to 43.8) Median lopinavir fold change (range) 0.70 (0.40 to 74.40) 0.80 (0.30 to 74.50) Median number of resistance-associateda: PI mutations 4 NNRTI mutations 1 NRTI mutations 2 Percentage of subjects with number of baseline primary protease inhibitor mutationsa: <=1 78% 80% 8% 9% >=3 13% 11% Median number of ARVs previously usedb: NRTIs 4 NNRTIs 1 PIs (excluding low-dose ritonavir) 1 Percentage of subjects resistantc to all availabled PIs at baseline, excluding darunavir 2% 3% Week 96 outcomes for subjects on darunavir/ritonavir 600/100 mg twice daily from trial TMC114-C214 are shown in Table 24. Table 24: Virologic Outcome of Randomized Treatment of Trial TMC114-C214 at 96 Weeks = total number of subjects with data; OBR=optimized background regimena Includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are >=50 copies in the 96-week window and patients who had change in their OBR that was not permitted by the protocol.b Window 90 to 102 Weeksc Includes patients who discontinued due to adverse event or death at any time point from Day through the time window if this resulted in no virologic data on treatment during the specified window.d Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL. Darunavir/Ritonavir 600/100 mg Twice Daily OBR N=298 Lopinavir/Ritonavir 400/100 mg Twice Daily OBR N=297 Virologic success HIV-1 RNA <50 copies/mL 58% 52% Virologic failurea 26% 33% No virologic data at Week 96 windowb Reasons Discontinued trial due to adverse event or deathc 7% 8% Discontinued trial for other reasonsd 8% 7% Missing data during window+ but on trial 1% <1% In trial TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the darunavir/ritonavir 600/100 mg twice daily arm and 93 cells/mm3 in the lopinavir/ritonavir 400/100 mg twice daily arm.TMC114-C213 and TMC114-C202TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with high level of PI resistance consisting of parts: an initial partially-blinded, dose-finding part and second long-term part in which all subjects randomized to darunavir/ritonavir received the recommended dose of 600/100 mg twice daily.HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on stable PI-containing regimen at screening for at least weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.The virologic response rate was evaluated in subjects receiving darunavir/ritonavir plus an OBR versus control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naive. Virologic response was defined as decrease in plasma HIV-1 RNA viral load of at least log10 versus baseline.In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the darunavir/ritonavir arm and the comparator PI arm (see Table 25). Table 25 compares the demographic and baseline characteristics between subjects in the darunavir/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of trials TMC114-C213 and TMC114-C202. Table 25: Demographic and Baseline Characteristics of Subjects in the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) OBR=optimized background regimena Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125-130b Based on phenotype (Antivirogram(R))c Commercially available PIs at the time of trial enrollment Darunavir/Ritonavir 600/100 mg Twice Daily OBR N=131 Comparator PI(s) OBR N=124 Demographic characteristics Median age (years) (range, years) 43 (27 to 73) 44 (25 to 65) Sex Male 89% 88% Female 11% 12% Race White 81% 73% Black 10% 15% Hispanic 7% 8% Baseline characteristics Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.61 4.49 Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 153 (3 to 776) 163 (3 to 1274) Percentage of patients with baseline viral load >100,000 copies/mL 24% 29% Percentage of patients with baseline CD4+ cell count <200 cells/mm3 67% 58% Median darunavir fold change 4.3 3.3 Median number of resistance-associateda: PI mutations 12 12 NNRTI mutations 1 NRTI mutations 5 Percentage of subjects with number of baseline primary protease inhibitor mutationsa: <=1 8% 9% 22% 21% >=3 70% 70% Median number of ARVs previously usedb: NRTIs 6 NNRTIs 1 PIs (excluding low-dose ritonavir) 5 Percentage of subjects resistantc to all availablec PIs at baseline, excluding tipranavir and darunavir 63% 61% Percentage of subjects with prior use of enfuvirtide 20% 17% Week 96 outcomes for subjects on the recommended dose darunavir/ritonavir 600/100 mg twice daily from the pooled trials TMC114-C213 and TMC114-C202 are shown in Table 26. Table 26: Outcomes of Randomized Treatment Through Week 96 of the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis) OBR=optimized background regimena Subjects who did not achieve at least confirmed 0.5 log10 HIV-1 RNA drop from baseline at Week 12b Subjects with an initial response (confirmed log10 drop in viral load), but without confirmed log10 drop in viral load at Week 96c Subjects who never reached confirmed log10 drop in viral load before Week 96 Randomized Trials TMC114-C213 and TMC114-C202 Darunavir/Ritonavir 600/100 mg Twice Daily OBR N=131 Comparator PI(s) +OBR N=124 Virologic responders confirmed at least log10 HIV-1 RNA below baseline through Week 96 (<50 copies/mL at Week 96) 57% (39%) 10% (9%) Virologic failures 29% 80% Lack of initial responsea 8% 53% Rebounderb 17% 19% Never suppressedc 4% 8% Death or discontinuation due to adverse events 9% 3% Discontinuation due to other reasons 5% 7% In the pooled trials TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were 1.69 log10 copies/mL in the arm receiving darunavir/ritonavir 600/100 mg twice daily and 0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving darunavir/ritonavir 600/100 mg twice daily (103 cells/mm3) than in the comparator PI arm (17 cells/mm3).. 14.4 Pediatric Patients. The pharmacokinetic profile, safety and antiviral activity of darunavir/ritonavir were evaluated in randomized, open-label, multicenter studies.TMC114-C212Treatment-experienced pediatric subjects between the ages of and less than 18 years and weighing at least 20 kg were stratified according to their weight (greater than or equal to 20 kg to less than 30 kg, greater than or equal to 30 kg to less than 40 kg, greater than or equal to 40 kg) and received darunavir tablets with either ritonavir capsules or oral solution plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs. Eighty patients were randomized and received at least one dose of darunavir/ritonavir. Pediatric subjects who were at risk of discontinuing therapy due to intolerance of ritonavir oral solution (e.g., taste aversion) were allowed to switch to the capsule formulation. Of the 44 pediatric subjects taking ritonavir oral solution, 23 subjects switched to the 100 mg capsule formulation and exceeded the weight-based ritonavir dose without changes in observed safety.The 80 randomized pediatric subjects had median age of 14 (range to less than 18 years), and were 71% male, 54% Caucasian, 30% Black, 9% Hispanic and 8% other. The mean baseline plasma HIV-1 RNA was 4.64 log10 copies/mL, and the median baseline CD4+ cell count was 330 cells/mm3(range: to 1505 cells/mm3). Overall, 38% of pediatric subjects had baseline plasma HIV-1 RNA >=100,000 copies/mL. Most pediatric subjects (79%) had previous use of at least one NNRTI and 96% of pediatric subjects had previously used at least one PI.Seventy-seven pediatric subjects (96%) completed the 24-week period. Of the patients who discontinued, one patient discontinued treatment due to an adverse event. An additional patients discontinued for other reasons, one patient due to compliance and another patient due to relocation.The proportion of pediatric subjects with HIV-1 RNA less than 400 copies/mL and less than 50 copies/mL was 64% and 50%, respectively. The mean increase in CD4+ cell count from baseline was 117 cells/mm3.TMC114-C228Treatment-experienced pediatric subjects between the ages of and less than years and weighing greater than or equal to 10 kg to less than 20 kg received darunavir oral suspension with ritonavir oral solution plus background therapy consisting of at least two active non- protease inhibitor antiretroviral drugs. Twenty-one subjects received at least one dose of darunavir/ritonavir.The 21 subjects had median age of 4.4 years (range to less than years), and were 48% male, 57% Black, 29%, Caucasian and 14% other. The mean baseline plasma HIV-1 was 4.34 log10 copies/mL, the median baseline CD4+ cell count was 927 106 cells/L (range: 209 to 2,429 106 cells/L) and the median baseline CD4+ percentage was 27.7% (range: 15.6% to 51.1%). Overall, 24% of subjects had baseline plasma HIV-1 RNA greater than or equal to 100,000 copies/mL. All subjects had used greater than or equal to NRTIs, 62% of subjects had used greater than or equal to NNRTI and 76% had previously used at least one HIV PI.Twenty subjects (95%) completed the 48 week period. One subject prematurely discontinued treatment due to vomiting assessed as related to ritonavir.The proportion of subjects with HIV-1 RNA less than 50 copies/mL at Week 48 was 71%. The mean increase in CD4+ percentage from baseline was 4%. The mean change in CD4+ cell count from baseline was 187 106 cells/L.TMC114-C230Treatment-naive pediatric subjects between the ages of 12 and less than 18 years and weighing at least 40 kg received the adult recommended dose of darunavir/ritonavir 800/100 mg once daily plus background therapy consisting of at least two non-protease inhibitor antiretroviral drugs.The 12 randomized pediatric subjects had median age of 14.4 years (range 12.6 to 17.3 years), and were 33.3% male, 58.3% Caucasian and 41.7% Black. The mean baseline plasma HIV-1 RNA was 4.72 log10 copies/mL, and the median baseline CD4+ cell count was 282 cells/mm3(range: 204 to 515 cells/mm3). Overall, 41.7% of pediatric subjects had baseline plasma HIV-1 RNA >=100,000 copies/mL. All subjects completed the 48 week treatment period.The proportion of subjects with HIV-1 RNA less than 50 copies/mL and less than 400 copies/mL was 83.3% and 91.7%, respectively. The mean increase in CD4+ cell count from baseline was 221 106 cells/L.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). (4). Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). (4). Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Examples of these drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below [see Drug Interactions (7.3)]. Due to the need for co-administration of darunavir with ritonavir, please refer to ritonavir prescribing information for description of ritonavir contraindications. Alpha 1-adrenoreceptor antagonist: alfuzosinAnti-gout: colchicine, in patients with renal and/or hepatic impairmentAntimycobacterial: rifampinAntipsychotics: lurasidone, pimozideCardiac Disorders: dronedarone, ivabradine, ranolazineErgot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovineHerbal product: St. Johns wort (Hypericum perforatum) Hepatitis direct acting antiviral: elbasvir/grazoprevirLipid modifying agents: lomitapide, lovastatin, simvastatinOpioid Antagonist: naloxegolPDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertensionSedatives/hypnotics: orally administered midazolam, triazolam. Alpha 1-adrenoreceptor antagonist: alfuzosin. Anti-gout: colchicine, in patients with renal and/or hepatic impairment. Antimycobacterial: rifampin. Antipsychotics: lurasidone, pimozide. Cardiac Disorders: dronedarone, ivabradine, ranolazine. Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine. Herbal product: St. Johns wort (Hypericum perforatum) Hepatitis direct acting antiviral: elbasvir/grazoprevir. Lipid modifying agents: lomitapide, lovastatin, simvastatin. Opioid Antagonist: naloxegol. PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension. Sedatives/hypnotics: orally administered midazolam, triazolam.

DESCRIPTION SECTION.

11 DESCRIPTION. Darunavir is an inhibitor of the human immunodeficiency virus (HIV-1) protease.Darunavir tablets contain the active ingredient darunavir, (present as darunavir ethanolate) which has the following chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1 (phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester monoethanolate. Its molecular formula is C27 H37 N3 O7 o C2 H5 OH and its molecular weight is 593.73. Darunavir ethanolate has the following structural formula:Darunavir ethanolate is white to off-white powder with solubility of approximately 0.15 mg per mL in water at 20C.Darunavir tablets 600 mg are available as orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side. Each 600 mg tablet contains darunavir 600 mg (present as darunavir ethanolate).Darunavir tablets 800 mg are available as dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side. Each 800 mg tablet contains darunavir 800 mg (present as darunavir ethanolate).During storage, partial conversion from ethanolate to hydrate may occur; however, this does not affect product quality or performance. Each tablet also contains the inactive ingredients colloidal silicon dioxide, crospovidone, hypromellose [800 mg] magnesium stearate and microcrystalline cellulose. Each tablet film-coating contains FD C yellow 6/ Sunset Yellow FCF Aluminium Lake [600 mg], iron oxide red [800 mg], polyethylene glycol 3350, polyvinyl alcohol-partially hydrolyzed, talc, and titanium dioxide. All strengths for darunavir are expressed in terms of the free form of darunavir.. Molecular Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Testing:In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with darunavir/ritonavir to assess drug susceptibility of the HIV-1 virus (2.1, 12.4)Monitor serum liver chemistry tests before and during therapy with darunavir/ritonavir. (2.1, 2.2, 5.2) Treatment-naive adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food. (2.3) Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (2.3) Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (2.4) Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of darunavir and ritonavir is based on body weight and should not exceed the adult dose. Darunavir tablets should be taken with ritonavir and with food. (2.5) Darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment. (2.6). Testing:In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with darunavir/ritonavir to assess drug susceptibility of the HIV-1 virus (2.1, 12.4)Monitor serum liver chemistry tests before and during therapy with darunavir/ritonavir. (2.1, 2.2, 5.2) In treatment-experienced patients, treatment history genotypic and/or phenotypic testing is recommended prior to initiation of therapy with darunavir/ritonavir to assess drug susceptibility of the HIV-1 virus (2.1, 12.4). Monitor serum liver chemistry tests before and during therapy with darunavir/ritonavir. (2.1, 2.2, 5.2). Treatment-naive adult patients and treatment-experienced adult patients with no darunavir resistance associated substitutions: 800 mg (one 800 mg tablet) taken with ritonavir 100 mg once daily and with food. (2.3). Treatment-experienced adult patients with at least one darunavir resistance associated substitution: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (2.3). Pregnant patients: 600 mg (one 600 mg tablet) taken with ritonavir 100 mg twice daily and with food. (2.4). Pediatric patients (3 to less than 18 years of age and weighing at least 10 kg): dosage of darunavir and ritonavir is based on body weight and should not exceed the adult dose. Darunavir tablets should be taken with ritonavir and with food. (2.5). Darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment. (2.6). 2.1 Testing Prior to Initiation of darunavir/ritonavir. In treatment-experienced patients, treatment history, genotypic and/or phenotypic testing is recommended to assess drug susceptibility of the HIV-1 virus [see Microbiology (12.4)]. Refer to Dosage and Administration (2.3), (2.4) and (2.5) for dosing recommendations.Appropriate laboratory testing such as serum liver biochemistries should be conducted prior to initiating therapy with darunavir/ritonavir [see Warnings and Precautions (5.2)].. 2.2 Monitoring During Treatment with darunavir/ritonavir. Patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases should be monitored for elevation in serum liver biochemistries, especially during the first several months of darunavir/ritonavir treatment [see Warnings and Precautions (5.2)].. 2.3 Recommended Dosage in Adult Patients. Darunavir must be co-administered with ritonavir to exert its therapeutic effect. Failure to correctly co-administer darunavir with ritonavir will result in plasma levels of darunavir that will be insufficient to achieve the desired antiviral effect and will alter some drug interactions.Patients who have difficulty swallowing darunavir tablets can use the 100 mg per mL darunavir oral suspension.Treatment-Naive Adult PatientsThe recommended oral dose of darunavir is 800 mg (one 800 mg tablet) taken with ritonavir 100 mg (one 100 mg tablet or capsule) once daily and with food.Treatment-Experienced Adult PatientsThe recommended oral dosage for treatment-experienced adult patients is summarized in Table 1.Baseline genotypic testing is recommended for dose selection. However, when genotypic testing is not feasible, darunavir 600 mg taken with ritonavir 100 mg twice daily is recommended. Table 1: Recommended Darunavir/Ritonavir Dosage in Treatment-Experienced Adult Patients aV11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V Formulation and Recommended Dosing Baseline Resistance Darunavir tablets with ritonavir tablets or capsule With no darunavir resistance associated substitutionsa One 800 mg darunavir tablet with one 100 mg ritonavir tablet/capsule, taken once daily with food With at least one darunavir resistance associated substitutionsa, or with no baseline resistance information One 600 mg darunavir tablet with one 100 mg ritonavir tablet/capsule, taken twice daily with food 2.4 Recommended Dosage During Pregnancy. The recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance.. 2.5 Recommended Dosage in Pediatric Patients (age to less than 18 years). Healthcare professionals should pay special attention to accurate dose selection of darunavir, transcription of the medication order, dispensing information and dosing instruction to minimize risk for medication errors, overdose, and underdose.Prescribers should select the appropriate dose of darunavir/ritonavir for each individual child based on body weight (kg) and should not exceed the recommended dose for adults.Before prescribing darunavir tablets, children weighing greater than or equal to 15 kg should be assessed for the ability to swallow tablets. If child is unable to reliably swallow tablet, the use of darunavir oral suspension should be considered.The recommended dose of darunavir/ritonavir for pediatric patients (3 to less than 18 years of age and weighing at least 10 kg is based on body weight (see Tables and 5) and should not exceed the recommended adult dose. Darunavir should be taken with ritonavir and with food.The recommendations for the darunavir/ritonavir dosage regimens were based on pediatric clinical trial data and population pharmacokinetic modeling and simulation [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Dosing Recommendations for Treatment-Naive Pediatric Patients or Antiretroviral Treatment-Experienced Pediatric Patients with No Darunavir Resistance Associated SubstitutionsPediatric patients weighing at least 15 kgPediatric patients weighing at least 15 kg can be dosed with darunavir tablets using the following table: Table 3: Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Naive or Treatment-Experienced with No Darunavir Resistance Associated Substitutionsa adarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Formulation: Darunavir tablet(s) and ritonavir capsules or tablets (100 mg) Body weight (kg) Dose: once daily with food Greater than or equal to 15 kg to less than 30 kg Darunavir 600 mg with ritonavir 100 mg Greater than or equal to 30 kg to less than 40 kg Darunavir 675 mg with ritonavir 100 mg Greater than or equal to 40 kg Darunavir 800 mg with ritonavir 100 mg Dosing Recommendations for Treatment-Experienced Pediatric Patients with At Least One Darunavir Resistance Associated SubstitutionsPediatric patients weighing at least 15 kgPediatric patients weighing at least 15 kg can be dosed darunavir tablets using the following table: Table 5:Recommended Dose for Pediatric Patients Weighing At Least 15 kg Who are Treatment-Experienced with At Least One Darunavir Resistance Associated Substitutiona adarunavir resistance associated substitutions: V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V Formulation: Darunavir tablet(s) and ritonavir tablets, capsules (100 mg) or oral solution (80 mg/mL) Body weight (kg) Dose: twice daily with food Greater than or equal to 15 kg to less than 30 kg Darunavir 375 mg with ritonavir 0.6 mL (48 mg) Greater than or equal to 30 kg to less than 40 kg Darunavir 450 mg with ritonavir 0.75 mL (60 mg) Greater than or equal to 40 kg Darunavir 600 mg with ritonavir 100 mg The use of darunavir/ritonavir in pediatric patients below years of age is not recommended [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)].. 2.6 Not Recommended in Patients with Severe Hepatic Impairment. No dosage adjustment is required in patients with mild or moderate hepatic impairment. No data are available regarding the use of darunavir/ritonavir when co-administered to subjects with severe hepatic impairment; therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 600 mg, and 800 mg (3). Tablets: 600 mg, and 800 mg (3). Darunavir Tablets600 mg: orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side.800 mg: dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side.. 600 mg: orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side.. 800 mg: dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side.

DRUG INTERACTIONS SECTION.

5.5 Risk of Serious Adverse Reactions due to Drug Interactions. Initiation of darunavir/ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving darunavir/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A.Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of darunavir/ritonavir, respectively. These interactions may lead to:Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.Clinically significant adverse reactions from greater exposures of darunavir/ritonavir.Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir /ritonavir.See Table 10 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during darunavir/ritonavir therapy; review concomitant medications during darunavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4 and Drug Interactions (7)].. Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.. Clinically significant adverse reactions from greater exposures of darunavir/ritonavir.. Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).. Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir /ritonavir.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of darunavir did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Darunavir Tablets, 600 mg are supplied as orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side.Darunavir Tablets, 800 mg are supplied as dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side.Darunavir Tablets are packaged in bottles in the following configuration: 600 mg tablets bottles of 60 (NDC 68180-345-07) 800 mg tablets bottles of 30 (NDC 68180-346-06), bottles of 90 (NDC 68180-346-09)StorageStore at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Keep darunavir tablets out of reach of children.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisDarunavir was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 150, 450 and 1000 mg/kg were administered to mice and doses of 50, 150 and 500 mg/kg was administered to rats. dose-related increase in the incidence of hepatocellular adenomas and carcinomas were observed in males and females of both species as well as an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of darunavir to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination, which predispose rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to darunavir (based on AUC) were between 0.4- and 0.7-fold (mice) and 0.7- and 1-fold (rats), relative to those observed in humans at the recommended therapeutic doses (600/100 mg twice daily or 800/100 mg once daily).Darunavir was not mutagenic or genotoxic in battery of in vitro and in vivo assays including bacterial reserve mutation (Ames), chromosomal aberration in human lymphocytes and in vivo micronucleus test in mice.Impairment of FertilityNo effects on fertility or early embryonic development were observed with darunavir in rats.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats [see DATA]. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving darunavir [see Use in Specific Populations (8.4)]. DataAnimal Data:Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Human experience of acute overdose with darunavir/ritonavir is limited. No specific antidote is available for overdose with darunavir. Treatment of overdose with darunavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Since darunavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Darunavir TabletsRx Only600 mgNDC 68180-345-07Bottle Label 60 TabletsImageDarunavir TabletsRx Only800 mgNDC 68180-346-06Bottle Label 30 TabletsImage. Bottle Label-600 mg. Bottle Label-800 mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Darunavir/ritonavir is not recommended in pediatric patients below years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions (5.10), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].The safety, pharmacokinetic profile, and virologic and immunologic responses of darunavir/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1 infected pediatric subjects to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, to less than 18 years of age) and TMC114-228 (21 subjects, to less than years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)]. Refer to Dosage and Administration (2.5) for twice-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg.In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)]. Once daily dosing recommendations for pediatric patients to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted darunavir exposures for the dosing recommendations in this age group [see Clinical Pharmacology (12.3)]. Please see Dosage and Administration (2.5) for once-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg.Juvenile Animal DataIn juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of to years of age), no deaths were observed with plasma exposure (in combination with ritonavir) times the human plasma exposure levels.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn thorough QT/QTc study in 40 healthy subjects, darunavir/ritonavir doses of 1.33 times the maximum recommended dose did not affect the QT/QTc interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in AdultsGeneral:Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When single dose of darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and darunavir/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients. Table 11: Population Pharmacokinetic Estimates of Darunavir at Darunavir/Ritonavir 800/100 mg Once Daily (Trial TMC114-C211, 48-Week Analysis and Trial TMC114-C229, 48-Week Analysis) and Darunavir/Ritonavir 600/100 mg Twice Daily (Trial TMC114-C214, 48-Week Analysis, Trial TMC114-C229, 48-Week Analysis and Integrated Data from Trials TMC114-C213 and TMC114-C202, Primary 24-Week Analysis) N=number of subjects with dataaAUC24h is calculated as AUC12h2. Parameter Darunavir/Ritonavir 800/100 mg once daily Darunavir/Ritonavir 600/100 mg twice daily TMC114-C211 N=335 TMC114-C229 N=280 TMC114-C214 N=285 TMC114-C229 N=278 TMC114-C213 TMC114-C202 (integrated data) N=119 AUC24h (ng.h/mL)a Mean +- Standard Deviation 93026 +- 27050 93334 +- 28626 116796 +- 33594 114302 +- 32681 124698 +- 32286 Median (Range) 87854 (45000 to 219240) 87788 (45456 to 236920) 111632 (64874 to 355360) 109401 (48934 to 323820) 123336 (67714 to 212980) C0h (ng/mL) Mean +- Standard Deviation 2282 +- 1168 2160 +- 1201 3490 +- 1401 3386 +- 1372 3578 +- 1151 Median (Range) 2041 (368 to 7242) 1896 (184 to 7881) 3307 (1517 to 13198) 3197 (250 to 11865) 3539 (1255 to 7368) Absorption and BioavailabilityDarunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with Tmax of approximately 2.5 to hours. The absolute oral bioavailability of single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.Effects of Food on Oral AbsorptionWhen darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).Distribution:Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).Metabolism: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. mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 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.Elimination:A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-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. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to darunavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.Risk SummaryProspective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see DATA]. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose [see DATA].Clinical ConsiderationsThe recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. DataHuman DataDarunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with background regimen was evaluated in clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6-12 weeks after delivery) and subjects discontinued before trial completion, subjects in the BID arm and subjects in the QD arm.The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6 to 12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [see Clinical Pharmacology (12.3)]. Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA >=50 copies/mL for 11% (2/18) of subjects and were missing for subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA >=50 copies/mL for none of the subjects and were missing for subjects (1 subject discontinued prematurely due to virologic failure).Darunavir/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 infected adults Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine. Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6.% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens..Animal DataReproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) to 15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD to 20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Contraindications (4) 4/2022.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONDARUNAVIR (dar-UE-na-vir) TABLETSRx only. Read this Patient Information before you start taking darunavir and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Also read the Patient Information leaflet for ritonavir.What is the most important information should know about DarunavirAsk your healthcare provider or pharmacist about medicines that should not be taken with darunavir. For more information, see Who should not take darunavir and What should tell my healthcare provider before taking darunavirDarunavir may cause liver problems. Some people taking darunavir in combination with ritonavir have developed liver problems, which may be life-threatening. Your healthcare provider should do blood tests before and during your darunavir and ritonavir combination treatment. If you have chronic hepatitis or infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider if you have any of the below signs and symptoms of liver problems.dark (tea colored) urineyellowing of your skin or whites of your eyespale colored stools (bowel movements)nauseavomitingpain or tenderness on your right side below your ribsloss of appetitetiredness Darunavir may cause severe or life-threatening skin reactions or rash.Sometimes these skin reactions and skin rashes can become severe and require treatment in hospital. Tell your healthcare provider right away if you develop rash. Stop taking darunavir and ritonavir combination treatment and tell your healthcare provider right away if you have any skin changes with symptoms below:fevertirednessmuscle or joint painblisters or skin lesionsmouth sores or ulcersred or inflamed eyes, like pink eye (conjunctivitis)Rash occurred more often in people taking darunavir and raltegravir together than with either drug separately but was generally mild.See What are the possible side effects of darunavir for more information about side effects.What is darunavirDarunavir is prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine used with ritonavir and other antiretroviral medicines to treat HIV-1 infection in adults and children years of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).Darunavir should not be used in children under years of age.When used with other antiretroviral medicines to treat HIV-1 infection, darunavir may help:reduce the amount of HIV-1 in your blood. This is called viral load.increase the number of CD4+ (T) cells in your blood that help fight off other infections.Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).Darunavir does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.Avoid doing things that can spread HIV-1 infection to others:Do not share or re-use needles or other injection equipment.Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.Ask your healthcare provider if you have any questions on how to prevent passing HIV to other people.Who should not take darunavirDo not take darunavir with any medicine that contains:alfuzosincolchicine, if you have liver or kidney problemsdronedaroneelbasvir and grazoprevirergot-containing medicines:dihydroergotamineergotamine tartratemethylergonovine ivabradine lomitapide lovastatin lurasidone midazolam, when taken by mouth naloxegol pimozide ranolazine rifampin sildenafil, when used for the treatment of pulmonary arterial hypertension (PAH) simvastatin St. Johns wort (Hypericum perforatum triazolamSerious problems can happen if you or your child take any of these medicines with darunavir. This is not complete list of medicines. Therefore, tell your healthcare provider about all medicines you take.What should tell my healthcare provider before taking darunavir Before taking darunavir, tell your healthcare provider if you:have liver problems, including hepatitis or hepatitis Care allergic to sulfa medicineshave high blood sugar (diabetes)have hemophiliahave any other medical conditionsare pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant while taking darunavir.Pregnancy Registry:There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take darunavir.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if darunavir can pass into your breast milk.Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, topical creams, vitamins, and herbal supplements. Some medicines interact with darunavir. Keep list of your medicines to show your healthcare provider and pharmacist.You can ask your healthcare provider or pharmacist for list of medicines that interact with darunavir.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take darunavir with other medicines.How should take Darunavir TabletsTake darunavir tablets exactly as your healthcare provider tells you.You must take ritonavir at the same time as darunavir.Do not change your dose or stop treatment with darunavir without talking to your healthcare provider.Take darunavir and ritonavir with food.If you have difficulty swallowing darunavir tablets, darunavir oral suspension is also available. Your healthcare provider will help decide whether darunavir tablets or oral suspension is right for you.If your child is taking darunavir, your childs healthcare provider will decide the right dose based on your childs weight. Your childs healthcare provider will tell you how much darunavir (tablets or oral suspension) and how much ritonavir (capsules, tablets or solution) your child should take. Your child should take darunavir with ritonavir with food. If your child does not tolerate ritonavir oral solution, ask your childs healthcare provider for advice.It is important that you do not miss or skip doses of darunavir during treatment.If you take too much darunavir, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of darunavirDarunavir may cause serious side effects, including:See What is the most important information should know about darunavir Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including darunavir can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often while taking darunavir.Changes in body fat can happen in people who take HIV-1 medicines. The changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including darunavir.The most common side effects of darunavir include:diarrheanausearashheadachestomach-area (abdominal) painvomittingTell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of darunavir.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Darunavir Tablets Store Darunavir Tablets at room temperature 77F (25C).Keep darunavir tablets and all medicines out of the reach of children. General information about the safe and effective use of Darunavir Tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use darunavir for condition for which it was not prescribed. Do not give darunavir to other people even if they have the same condition you have. It may harm them.This leaflet summarizes the most important information about darunavir. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about darunavir that is written for health professionals. For more information, call 1-800-399-2561 or visit www.lupinpharmaceuticals.com.What are the ingredients in Darunavir TabletsActive ingredient: darunavirInactive ingredients:Darunavir Tablets, 600 mg: colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, and the film-coating contains FD C yellow 6/sunset yellow FCF aluminium lake, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc and titanium dioxide.Darunavir Tablets, 800 mg: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, and the film-coating contains iron oxide red, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc and titanium dioxide.This Patient Information has been approved by the U.S. Food and Drug Administration.All brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products.Manufactured for: Lupin Pharmaceuticals, Inc.Baltimore, Maryland 21202United StatesManufactured by:Lupin LimitedNagpur 441 108INDIARevised: January 2024 ID:272686. Ask your healthcare provider or pharmacist about medicines that should not be taken with darunavir. For more information, see Who should not take darunavir and What should tell my healthcare provider before taking darunavir. Darunavir may cause liver problems. Some people taking darunavir in combination with ritonavir have developed liver problems, which may be life-threatening. Your healthcare provider should do blood tests before and during your darunavir and ritonavir combination treatment. If you have chronic hepatitis or infection, your healthcare provider should check your blood tests more often because you have an increased chance of developing liver problems. Tell your healthcare provider if you have any of the below signs and symptoms of liver problems.dark (tea colored) urineyellowing of your skin or whites of your eyespale colored stools (bowel movements)nauseavomitingpain or tenderness on your right side below your ribsloss of appetitetiredness dark (tea colored) urine. yellowing of your skin or whites of your eyes. pale colored stools (bowel movements). nausea. vomiting. pain or tenderness on your right side below your ribs. loss of appetite. tiredness. Darunavir may cause severe or life-threatening skin reactions or rash.Sometimes these skin reactions and skin rashes can become severe and require treatment in hospital. Tell your healthcare provider right away if you develop rash. Stop taking darunavir and ritonavir combination treatment and tell your healthcare provider right away if you have any skin changes with symptoms below:fevertirednessmuscle or joint painblisters or skin lesionsmouth sores or ulcersred or inflamed eyes, like pink eye (conjunctivitis). fever. tiredness. muscle or joint pain. blisters or skin lesions. mouth sores or ulcers. red or inflamed eyes, like pink eye (conjunctivitis). reduce the amount of HIV-1 in your blood. This is called viral load.. increase the number of CD4+ (T) cells in your blood that help fight off other infections.. Do not share or re-use needles or other injection equipment.. Do not share personal texts that can have blood or body fluids on them, like toothbrushes and razor blades.. Do not have any kind of sex without protection. Always practice safe sex by using latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.. alfuzosin. colchicine, if you have liver or kidney problems. dronedarone. elbasvir and grazoprevir. ergot-containing medicines:dihydroergotamineergotamine tartratemethylergonovine dihydroergotamine. ergotamine tartrate. methylergonovine. ivabradine. lomitapide. lovastatin. lurasidone. midazolam, when taken by mouth. naloxegol. pimozide. ranolazine. rifampin. sildenafil, when used for the treatment of pulmonary arterial hypertension (PAH). simvastatin. St. Johns wort (Hypericum perforatum ). triazolam. have liver problems, including hepatitis or hepatitis C. are allergic to sulfa medicines. have high blood sugar (diabetes). have hemophilia. have any other medical conditions. are pregnant or plan to become pregnant. Tell your healthcare provider if you become pregnant while taking darunavir.Pregnancy Registry:There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. Pregnancy Registry:There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.. are breastfeeding or plan to breastfeed. Do not breastfeed if you take darunavir.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if darunavir can pass into your breast milk.Talk to your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. It is not known if darunavir can pass into your breast milk.. Talk to your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with darunavir.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take darunavir with other medicines.. Take darunavir tablets exactly as your healthcare provider tells you.. You must take ritonavir at the same time as darunavir.. Do not change your dose or stop treatment with darunavir without talking to your healthcare provider.. Take darunavir and ritonavir with food.. If you have difficulty swallowing darunavir tablets, darunavir oral suspension is also available. Your healthcare provider will help decide whether darunavir tablets or oral suspension is right for you.. If your child is taking darunavir, your childs healthcare provider will decide the right dose based on your childs weight. Your childs healthcare provider will tell you how much darunavir (tablets or oral suspension) and how much ritonavir (capsules, tablets or solution) your child should take. Your child should take darunavir with ritonavir with food. If your child does not tolerate ritonavir oral solution, ask your childs healthcare provider for advice.. It is important that you do not miss or skip doses of darunavir during treatment.. If you take too much darunavir, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about darunavir Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including darunavir can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your healthcare provider if you notice an increase in thirst or urinate often while taking darunavir.. Changes in body fat can happen in people who take HIV-1 medicines. The changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.. Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including darunavir.. diarrhea. nausea. rash. headache. stomach-area (abdominal) pain. vomitting.

SPL UNCLASSIFIED SECTION.

Darunavir Tablets600 mg: orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side.800 mg: dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side.. 600 mg: orange colored, oval shaped, film-coated tablets debossed with LU on one side and A42 on the other side.. 800 mg: dark red colored, oval shaped, film-coated tablets debossed with LU on one side and A46 on the other side.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Total darunavir exposures were generally lower during pregnancy compared to postpartum period. The reduction in darunavir exposures during pregnancy were greater for once daily dosing compared to the twice daily dosing regimen. (8.1, 12.3)Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2)Pediatrics: Not recommended for patients less than years of age. (8.4). Pregnancy: Total darunavir exposures were generally lower during pregnancy compared to postpartum period. The reduction in darunavir exposures during pregnancy were greater for once daily dosing compared to the twice daily dosing regimen. (8.1, 12.3). Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.2). Pediatrics: Not recommended for patients less than years of age. (8.4). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to darunavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.Risk SummaryProspective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Available limited data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see DATA]. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose [see DATA].Clinical ConsiderationsThe recommended dosage in pregnant patients is darunavir 600 mg taken with ritonavir 100 mg twice daily with food.Darunavir 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on stable darunavir 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom change to twice daily darunavir 600 mg with ritonavir 100 mg may compromise tolerability or compliance [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. DataHuman DataDarunavir/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with background regimen was evaluated in clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6-12 weeks after delivery) and subjects discontinued before trial completion, subjects in the BID arm and subjects in the QD arm.The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6 to 12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [see Clinical Pharmacology (12.3)]. Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA >=50 copies/mL for 11% (2/18) of subjects and were missing for subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA >=50 copies/mL for none of the subjects and were missing for subjects (1 subject discontinued prematurely due to virologic failure).Darunavir/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of darunavir/ritonavir in HIV-1 infected adults Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine. Based on prospective reports to the APR of over 980 exposures to darunavir-containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6.% (95% CI: 2.3% to 5.3.%) with first trimester exposure to darunavir-containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens..Animal DataReproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) to 15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD to 19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD to 20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats [see DATA]. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving darunavir [see Use in Specific Populations (8.4)]. DataAnimal Data:Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.. 8.3 Females and Males of Reproductive Potential. ContraceptionUse of darunavir may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia [see Drug Interactions (7.3)].. 8.4 Pediatric Use. Darunavir/ritonavir is not recommended in pediatric patients below years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Warnings and Precautions (5.10), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].The safety, pharmacokinetic profile, and virologic and immunologic responses of darunavir/ritonavir administered twice daily were evaluated in treatment-experienced HIV-1 infected pediatric subjects to less than 18 years of age and weighting at least 10 kg. These subjects were evaluated in clinical trials TMC114-C212 (80 subjects, to less than 18 years of age) and TMC114-228 (21 subjects, to less than years of age) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)]. Refer to Dosage and Administration (2.5) for twice-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg.In clinical trial TMC114-C230, the safety, pharmacokinetic profile and virologic and immunologic responses of darunavir/ritonavir administered once daily were evaluated in treatment-naive HIV-1 infected pediatric subjects 12 to less than 18 years of age (12 subjects) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.4)]. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults [see Adverse Reactions (6.1)]. Once daily dosing recommendations for pediatric patients to less than 12 years of age were derived using population pharmacokinetic modeling and simulation. Although darunavir/ritonavir once daily dosing pediatric trial was not conducted in children less than 12 years of age, there is sufficient clinical safety data to support the predicted darunavir exposures for the dosing recommendations in this age group [see Clinical Pharmacology (12.3)]. Please see Dosage and Administration (2.5) for once-daily dosing recommendations for pediatric subjects to less than 18 years of age and weighing at least 10 kg.Juvenile Animal DataIn juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of to years of age), no deaths were observed with plasma exposure (in combination with ritonavir) times the human plasma exposure levels.. 8.5 Geriatric Use. Clinical studies of darunavir did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. In general, caution should be exercised in the administration and monitoring of darunavir in elderly patients, reflecting the greater frequency of decreased hepatic function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment. No dosage adjustment of darunavir/ritonavir is necessary for patients with either mild or moderate hepatic impairment. No pharmacokinetic or safety data are available regarding the use of darunavir/ritonavir in subjects with severe hepatic impairment. Therefore, darunavir/ritonavir is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected subjects with moderate renal impairment (CrCL between 30 to 60 mL/min, n=20). No pharmacokinetic data are available in HIV-1-infected patients with severe renal impairment or end stage renal disease; however, because the renal clearance of darunavir is limited, decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. Post-marketing cases of liver injury, including some fatalities, have been reported. (5.2)Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported. Discontinue treatment if severe reaction develops. (5.3)Use with caution in patients with known sulfonamide allergy. (5.4)Patients may develop new onset diabetes mellitus or hyperglycemia. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. (5.6)Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome. (5.7, 5.8)Patients with hemophilia may develop increased bleeding events. (5.9)Darunavir/ritonavir is not recommended in pediatric patients below years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age. (5.10). Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. Monitor liver function before and during therapy, especially in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases. Post-marketing cases of liver injury, including some fatalities, have been reported. (5.2). Skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis, have been reported. Discontinue treatment if severe reaction develops. (5.3). Use with caution in patients with known sulfonamide allergy. (5.4). Patients may develop new onset diabetes mellitus or hyperglycemia. Initiation or dose adjustments of insulin or oral hypoglycemic agents may be required. (5.6). Patients may develop redistribution/accumulation of body fat or immune reconstitution syndrome. (5.7, 5.8). Patients with hemophilia may develop increased bleeding events. (5.9). Darunavir/ritonavir is not recommended in pediatric patients below years of age in view of toxicity and mortality observed in juvenile rats dosed with darunavir up to days 23 to 26 of age. (5.10). 5.1 Importance of Co-administration with Ritonavir. Darunavir must be co-administered with ritonavir and food to achieve the desired antiviral effect. Failure to administer darunavir with ritonavir and food may result in loss of efficacy of darunavir.Please refer to ritonavir prescribing information for additional information on precautionary measures.. 5.2 Hepatotoxicity. Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir/ritonavir. During the clinical development program (N=3063), hepatitis was reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.Post-marketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis or co-infection, and/or developing immune reconstitution syndrome. causal relationship with darunavir/ritonavir therapy has not been established.Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pre-treatment elevations of transaminases, especially during the first several months of darunavir/ritonavir treatment.Evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on darunavir/ritonavir should prompt consideration of interruption or discontinuation of treatment.. 5.3 Severe Skin Reactions. During the clinical development program (n=3063), severe skin reactions, accompanied by fever and/or elevations of transaminases in some cases, have been reported in 0.4% of subjects. Stevens-Johnson Syndrome was rarely (less than 0.1%) reported during the clinical development program. During post-marketing experience toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis have been reported. Discontinue darunavir/ritonavir immediately if signs or symptoms of severe skin reactions develop. These can include but are not limited to severe rash or rash accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.Rash (all grades, regardless of causality) occurred in 10.3% of subjects treated with darunavir/ritonavir [see Adverse Reactions (6)]. Rash was mostly mild-to-moderate, often occurring within the first four weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in subjects using darunavir/ritonavir was 0.5%.Rash occurred more commonly in treatment-experienced subjects receiving regimens containing darunavir/ritonavir raltegravir compared to subjects receiving darunavir/ritonavir without raltegravir or raltegravir without darunavir/ritonavir. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.. 5.4 Sulfa Allergy. Darunavir contains sulfonamide moiety. Darunavir should be used with caution in patients with known sulfonamide allergy. In clinical studies with darunavir/ritonavir, the incidence and severity of rash were similar in subjects with or without history of sulfonamide allergy.. 5.5 Risk of Serious Adverse Reactions due to Drug Interactions. Initiation of darunavir/ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving darunavir/ritonavir, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A.Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of darunavir/ritonavir, respectively. These interactions may lead to:Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.Clinically significant adverse reactions from greater exposures of darunavir/ritonavir.Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir /ritonavir.See Table 10 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during darunavir/ritonavir therapy; review concomitant medications during darunavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant drugs [see Contraindications (4 and Drug Interactions (7)].. Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.. Clinically significant adverse reactions from greater exposures of darunavir/ritonavir.. Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).. Loss of therapeutic effect of darunavir/ritonavir and possible development of resistance from lower exposures of darunavir /ritonavir.. 5.6 Diabetes Mellitus/Hyperglycemia. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor (PI) therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued PI therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationships between PI therapy and these events have not been established.. 5.7 Fat Redistribution. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.8 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including darunavir. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral treatment.. 5.9 Hemophilia. There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type and treated with PIs. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced if treatment had been discontinued. causal relationship between PI therapy and these episodes has not been established.. 5.10 Not Recommended in Pediatric Patients Below Years of Age. Darunavir/ritonavir in pediatric patients below years of age is not recommended in view of toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1000 mg/kg) up to days 23 to 26 of age [see Use in Specific Populations (8.1 and 8.4) and Clinical Pharmacology (12.3)].