CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Fosamprenavir is an HIV-1 antiretroviral agent [see Microbiology (12.4)]. 12.3 Pharmacokinetics. The pharmacokinetic properties of amprenavir after administration of fosamprenavir, with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-1-infected subjects; no substantial differences in steady-state amprenavir concentrations were observed between the populations. The pharmacokinetic parameters of amprenavir after administration of fosamprenavir (with and without concomitant ritonavir) are shown in Table 7. Table 7. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in AdultsRegimenCmax (mcg/mL)Tmax (hours)Data shown are median (range).AUC24 (mcgoh/mL)Ctau Ctau is the concentration at the end of the dose interval.(mcg/mL)Fosamprenavir1,400 mg Twice Daily(n 22)HIV-infected adults. 4.82(4.06-5.72)1.3(0.8-4.0)33.0AUC24 was calculated from AUC12 summary data 2. (27.6-39.2)0.35(0.27-0.46)Fosamprenavir1,400 mg Once Daily plus Ritonavir 200 mg Once Daily(n 22)Healthy adults. 7.24(6.32-8.28)2.1(0.8-5.0)69.4(59.7-80.8)1.45(1.16-1.81)Fosamprenavir1,400 mg Once Daily plus Ritonavir 100 mg Once Daily(n 36) 7.93(7.25-8.68)1.5(0.75-5.0)66.4(61.1-72.1)0.86(0.74-1.01)Fosamprenavir700 mg Twice Daily plus Ritonavir 100 mg Twice Daily(n 24) 6.08(5.38-6.86)1.5(0.75-5.0)79.2(69.0-90.6)2.12(1.77-2.54)The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1. Figure 1. Mean (+-SD) Steady-State Plasma Amprenavir Concentrations and Mean EC50 Values Against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) Absorption. After administration of single dose of fosamprenavir to HIV-1-infected subjects, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of single 1,400-mg dose in the fasted state, fosamprenavir calcium oral suspension (50 mg per mL) and fosamprenavir calcium tablets (700 mg) provided similar amprenavir exposures (AUC); however, the Cmax of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet. Amprenavir is both substrate for and inducer of P-glycoprotein.. Effects of Food on Oral Absorption. Administration of single 1,400 mg-dose of fosamprenavir calcium tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC0- [see Dosage and Administration (2)]. Distribution. In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations. Metabolism. After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the CYP3A4 enzyme system. The major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces. Elimination. Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours. Specific Populations. Patients with Hepatic Impairment. The pharmacokinetics of amprenavir have been studied after the administration of fosamprenavir in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following weeks of dosing with fosamprenavir plus ritonavir, the AUC of amprenavir was increased by approximately 22% in subjects with mild hepatic impairment, by approximately 70% in subjects with moderate hepatic impairment, and by approximately 80% in subjects with severe hepatic impairment compared with HIV-1-infected subjects with normal hepatic function. Protein binding of amprenavir was decreased in subjects with hepatic impairment. The unbound fraction at hours (approximate Cmax) ranged between decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (Cmin) increased from 50% to 102% [see Dosage and Administration (2.4)]. The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE(R) capsules to adult subjects with hepatic impairment. Following administration of single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in subjects with moderate cirrhosis and by approximately 4.5-fold in subjects with severe cirrhosis compared with healthy volunteers [see Dosage and Administration (2.4)]. Patients with Renal Impairment. The impact of renal impairment on amprenavir elimination in adults has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir. Pregnant Women Amprenavir pharmacokinetics were studied in pregnant women receiving fosamprenavir (700 mg) plus ritonavir (100 mg) twice daily during the second trimester (n 6) or third trimester (n 9) and postpartum (n 9). Compared to postpartum, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester (Table 8). This decrease results in amprenavir concentrations that are within the range observed across regimens of fosamprenavir in non-pregnant adults and lower concentrations compared with fosamprenavir (700 mg) plus ritonavir (100 mg) twice daily in non-pregnant adults (Table 7, Table 8). This decrease is not expected to be considered clinically relevant in patients who are virologically suppressed; however, viral load should be monitored closely to ensure viral suppression is maintained [see Dosage and Administration (2.2), Use in Specific Populations (8.1)]. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n 7) was 0.27 (0.24 to 0.30).Table 8. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Pregnant Women Receiving Fosamprenavir with RitonavirPharmacokineticParameterFosamprenavir 700 mg Twice Daily plus Ritonavir 100 mg Twice DailySecond Trimester(n 6)Third Trimester(n 9)Postpartum(n 9)AUC12 (mcgoh/mL)26.0(19.5, 34.6)30.1(21.6, 41.9)39.9(31.9, 50.1)AUC24 (mcgoh/mL)AUC24 was calculated from AUC12 summary data 2. 52.0(39.0, 69.2)60.2(43.2, 83.8)79.8(63.8, 100.2)Cmax (mcg/mL)4.19(3.19, 5.51)5.36(3.98, 7.22)6.65(5.24, 8.44)Ctau (mcg/mL)Ctau represents the concentration at the end of the dose interval. 1.31(0.97, 1.77)1.34(0.95, 1.89)2.03(1.46, 2.83). Pediatric Patients. The pharmacokinetics of amprenavir following administration of fosamprenavir calcium oral suspension and fosamprenavir calcium tablets, with or without ritonavir, have been studied in total of 212 HIV-1-infected pediatric subjects enrolled in trials. Fosamprenavir without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged to years. Fosamprenavir with ritonavir was administered as fosamprenavir 30 mg per kg plus ritonavir mg per kg once daily to children aged to 18 years and as fosamprenavir 18 to 60 mg per kg plus ritonavir to 10 mg per kg twice daily to children aged at least weeks to 18 years; body weights ranged from to 103 kg.Amprenavir apparent clearance decreased with increasing weight. Weight-adjusted apparent clearance was higher in children younger than years, suggesting that younger children require higher mg-per-kg dosing of fosamprenavir.The pharmacokinetics of fosamprenavir calcium oral suspension in protease inhibitor-naive infants younger than months (n 9) receiving fosamprenavir 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC12 and Cmin than adults receiving twice-daily fosamprenavir 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC12, Cmax, and Cmin were 26.6 mcgohour per mL, 6.25 mcg per mL, and 0.86 mcg per mL, respectively. Because of expected low amprenavir exposure and requirement for large volume of drug, twice-daily dosing of fosamprenavir alone (without ritonavir) in pediatric subjects younger than years was not studied.Pharmacokinetic parameters for fosamprenavir administered with food and with ritonavir in this patient population at the recommended weight-band-based dosage regimens are provided in Table 9. Table 9. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters by Weight in Pediatric and Adolescent Subjects Aged at Least Weeks to 18 Years Receiving Fosamprenavir with RitonavirWeightRecommended Dosage RegimenCmax AUC24 Cmin n(mcg/mL)n(mcgoh/mL)n(mcg/mL)< 11 kgFosamprenavir 45 mg/kg plus Ritonavir mg/kg twice daily126.00(3.88, 9.29)1257.3(34.1, 96.2)271.65(1.22, 2.24)11 kg < 15 kgFosamprenavir 30 mg/kg plus Ritonavir mg/kg twice dailyNot studiedRecommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis. 15 kg < 20 kgFosamprenavir 23 mg/kg plus Ritonavir mg/kg twice daily59.54(4.63, 19.7)5121(54.2, 269)93.56(2.33, 5.43)20 kg < 39 kgFosamprenavir 18 mg/kg plus Ritonavir mg/kg twice daily136.24(5.01, 7.77)1297.9(77.0, 124)232.54(2.11, 3.06)>= 39 kgFosamprenavir 700 mg plus Ritonavir 100 mg twice daily155.03(4.04, 6.26)1572.3(59.6, 87.6)421.98(1.72, 2.29)Subjects aged to younger than years receiving fosamprenavir 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir Cmax (n 9), AUC12 (n 9), and Cmin (n 19) of 7.15 (5.05, 10.1), 22.3 (15.3, 32.6), and 0.513 (0.384, 0.686), respectively.. Geriatric Patients. The pharmacokinetics of amprenavir after administration of fosamprenavir to patients older than 65 years have not been studied [see Use in Specific Populations (8.5)]. Male and Female Patients. The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between males and females. Racial Groups. The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between blacks and non-blacks. Drug Interaction Studies. [See Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7).]Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Amprenavir is both substrate for and inducer of P-glycoprotein. Drug interaction trials were performed with fosamprenavir and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of fosamprenavir on other drugs). In addition, since fosamprenavir delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from trials with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, [see Drug Interactions (7)]. Table 10. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of Fosamprenavir in the Presence of the Coadministered Drug(s) Increase; Decrease; <-> No change or less than or equal to 10%), NA Not applicable.Coadministered Drug(s) and Dose(s)Dose of FosamprenavirConcomitant medication is also shown in this column where appropriate.n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)Cmax AUCCmin Antacid (MAALOX TC) 30-mL single dose1,400-mg single dose3035(24 to 42)18(9 to 26)14(7 to 39)Atazanavir 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days22<-><-><->Atorvastatin 10 mg once daily for days 1,400 mg twice daily for weeks1618(34 to 1)27(41 to 12)12(27 to 6)Atorvastatin 10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-><->Efavirenz 600 mg once daily for weeks 1,400 mg once daily plus ritonavir 200 mg once daily for weeks16<->13(30 to 7)36(8 to 56)Efavirenz 600 mg once daily plus additional ritonavir 100 mg once daily for weeks 1,400 mg once daily plus ritonavir 200 mg once daily for weeks1618(1 to 38)11(0 to 24)<->Efavirenz 600 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><->17(4 to 29)Esomeprazole 20 mg once daily for weeks 1,400 mg twice daily for weeks25<-><-><->Esomeprazole 20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><-><->Ethinyl estradiol/norethindrone 0.035 mg/0.5 mg once daily for 21 days 700 mg twice daily plus ritonavirRitonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control. 100 mg twice daily for 21 days25<->Compared with historical control. <-> <-> KetoconazoleSubjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for days15<-><-><->Lopinavir/ritonavir 533 mg/133 mg twice daily 1,400 mg twice daily for weeks1813Compared with fosamprenavir 700 mg/ritonavir 100 mg twice daily for weeks. 26 42 Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks1858(42 to 70)63(51 to 72)65(54 to 73)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 20 days1434(25 to 41)35(29 to 41)36(27 to 43)Maraviroc300 mg once daily for 10 days1,400 mg once daily plus ritonavir 100 mg once daily for 20 days1429(20 to 38)30(23 to 36)15(3 to 25)Methadone 70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19<-> <-> <-> Nevirapine 200 mg twice daily for weeksSubjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for weeks1725(37 to 10)33(45 to 20)35(50 to 15)Nevirapine 200 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks17<->11(23 to 3)19(32 to 4)Phenytoin 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days13<->20(8 to 34)19(6 to 33)Raltegravir 400 mg twice daily for 14 days 1,400 mg twice daily for 14 days (fasted)1427(46 to <->)36(53 to 13)43Clast (C12 or C24 h). (59 to 21)1,400 mg twice daily for 14 daysDoses of fosamprenavir and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days. 1415(27 to 1)17(27 to 6)32 (53 to 1)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days (fasted)1414(39 to 20)17(38 to 12)20 (45 to 17)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days 1225(42 to 2)25(44 to <->)33 (52 to 7)Raltegravir 400 mg twice daily for 14 days 1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted)1318(34 to <->)24(41 to <->)50 (64 to 31)1,400 mg once daily plus ritonavir 100 mg once daily for 14 days 1427(1 to 62)13(7 to 38)17 (45 to 26)Ranitidine 300-mg single dose (administered hour before fosamprenavir) 1,400-mg single dose3051(43 to 58)30(22 to 37)<->(19 to 21)Rifabutin 150 mg every other day for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1536 (18 to 55)35 (17 to 56)17 (1 to 39)Tenofovir 300 mg once daily for to 48 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for to 48 weeks45NANA<->Compared with parallel control group. Tenofovir 300 mg once daily for to 48 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for to 48 weeks60NANA<-> Table 11. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s) Increase; Decrease; <-> No change or less than 10%); NA Cmin not calculated for single-dose trial.Coadministered Drug(s) and Dose(s)Dose of AGENERASECompared with parallel control group.n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)Cmax AUCCmin Abacavir300 mg twice daily for to weeks 900 mg twice daily for to weeks4<-> <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice daily for days1215(1 to 31)18(8 to 29)39(31 to 47)Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days940Median percent change; confidence interval not reported. 130 125 Ethinyl estradiol/norethindrone 0.035 mg/1 mg for cycle 1,200 mg twice daily for 28 days10<->22(35 to 8)20(41 to 8)Indinavir 800 mg times day for weeks (fasted) 750 or 800 mg times day for weeks (fasted)918(13 to 58)33(2 to 73)25(27 to 116)Ketoconazole400-mg single dose 1,200-mg single dose1216(25 to 6)31(20 to 42)NALamivudine150-mg single dose 600-mg single dose11<-><->NAMethadone44 to 100 mg once daily for> 30 days 1,200 mg twice daily for 10 days1627Compared with historical data. 30 25 Nelfinavir750 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)614(38 to 20)<->189(52 to 448)Rifabutin300 mg once daily for 10 days 1,200 mg twice daily for 10 days5<->15(28 to 0)15(38 to 17)Rifampin300 mg once daily for days 1,200 mg twice daily for days1170(76 to 62)82(84 to 78)92(95 to 89)Saquinavir800 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)737(54 to 14)32(49 to 9)14(52 to 54)Zidovudine300-mg single dose 600-mg single dose12<->13(2 to 31)NATable 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Fosamprenavir Increase; Decrease; <-> No change or less than 10%); ND Interaction cannot be determined as Cmin was below the lower limit of quantitation.Coadministered Drug(s) and Dose(s)Dose of FosamprenavirConcomitant medication is also shown in this column where appropriate.n% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)Cmax AUCCmin Atazanavir 300 mg once daily for 10 daysComparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily for 10 days. 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days2124(39 to 6)22(34 to 9)<->Atorvastatin 10 mg once daily for days 1,400 mg twice daily for weeks16304(205 to 437)130(100 to 164)10(27 to 12)Atorvastatin 10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16184(126 to 257)153(115 to 199)73(45 to 108)Esomeprazole 20 mg once daily for weeks 1,400 mg twice daily for weeks25<->55(39 to 73)NDEsomeprazole 20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><->NDEthinyl estradiolAdministered as combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg. 0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days2528(21 to 35)37(30 to 42)NDDolutegravir50 mg once daily700 mg twice daily plus ritonavir 100 mg twice daily1224(8 to 37)35(22 to 46)49(37 to 59)KetoconazoleSubjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for days1525(0 to 56)169(108 to 248)NDLopinavir/ritonavirData represent lopinavir concentrations. 533 mg/133 mg twice daily for weeks 1,400 mg twice daily for weeks18<->Compared with lopinavir 400 mg/ritonavir 100 mg twice daily for weeks. <-> <-> Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1830(15 to 47)37(20 to 55)52(28 to 82)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 20 days1452(27 to 82)149(119 to 182)374(303 to 457)Maraviroc300 mg once daily for 10 days1,400 mg once daily plus ritonavir 100 mg once daily for 20 days1445(20 to 74)126(99 to 158)80(53 to 113)Methadone 70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19R-Methadone (active)21Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged. (30 to 12)18 (27 to 8)11 (21 to 1)S-Methadone (inactive)43 (49 to 37)43 (50 to 36)41 (49 to 31)Nevirapine 200 mg twice daily for weeksSubjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for weeks1725(14 to 37)29(19 to 40)34(20 to 49)Nevirapine 200 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1713(3 to 24)14(5 to 24)22(9 to 35)Norethindrone 0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days2538(32 to 44)34(30 to 37)26(20 to 32)Phenytoin 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days1420(12 to 27)22(17 to 27)29(23 to 34)Rifabutin 150 mg every other day for weeksComparison arm of rifabutin 300 mg once daily for weeks. AUC is AUC(0-48 h). 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1514(28 to 4)<->28(12 to 46)(25-O-desacetylrifabutin metabolite)579(479 to 698)1,120(965 to 1,300)2,510(1,910 to 3,300)Rifabutin 25-O-desacetylrifabutin metaboliteNA64(46 to 84)NARosuvastatin10-mg single dose700 mg twice daily plus ritonavir 100 mg twice daily for days458NATable 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE Increase; Decrease; <-> No change or less than 10%); NA Cmin not calculated for single-dose trial; ND Interaction cannot be determined as Cmin was below the lower limit of quantitation.Coadministered Drug(s) and Dose(s)Dose of AGENERASEn% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)Cmax AUCCmin Abacavir300 mg twice daily for to weeks 900 mg twice daily for to weeks4<->Compared with historical data. <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice daily for days1210(24 to 7)<-><->Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days947Median percent change; confidence interval not reported. 61 88 Ethinyl estradiol0.035 mg for cycle 1,200 mg twice daily for 28 days10<-><->32(3 to 79)Indinavir800 mg times day for weeks (fasted) 750 mg or 800 mg times day for weeks (fasted)922 38 27 Ketoconazole400-mg single dose 1,200-mg single dose1219(8 to 33)44(31 to 59)NALamivudine150-mg single dose 600-mg single dose11<-><->NAMethadone44 mg to 100 mg once daily for 30 days 1,200 mg twice daily for 10 days16R-Methadone (active)25(32 to 18)13(21 to 5)21(32 to 9)S-Methadone (inactive)48(55 to 40)40(46 to 32)53(60 to 43)Nelfinavir750 mg times day for weeks (fed) 750 mg or 800 mg times day for weeks (fed)612 15 14 Norethindrone1 mg for cycle 1,200 mg twice daily for 28 days10<->18(1 to 38)45(13 to 88)Rifabutin300 mg once daily for 10 days 1,200 mg twice daily for 10 days5119(82 to 164)193(156 to 235)271(171 to 409)Rifampin300 mg once daily for days 1,200 mg twice daily for days11<-><->NDSaquinavir800 mg times day for weeks (fed) 750 mg or 800 mg times day for weeks (fed)721 19 48 Zidovudine300-mg single dose 600-mg single dose1240(14 to 71)31(19 to 45)NA. Figure 1. Mean (+-SD) Steady-State Plasma Amprenavir Concentrations and Mean EC50 Values Against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum). 12.4 Microbiology Mechanism of Action. Fosamprenavir is prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles. Antiviral Activity. Fosamprenavir has little or no antiviral activity in cell culture. The antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, H9) and in peripheral blood lymphocytes in cell culture. The 50% effective concentration (EC50) of amprenavir ranged from 0.012 to 0.08 microM in acutely infected cells and was 0.41 microM in chronically infected cells (1 microM 0.50 mcg per mL). The median EC50 value of amprenavir against HIV-1 isolates from clades to was 0.00095 microM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC50 values for amprenavir against monocytes/macrophage tropic HIV-1 isolates (clade B) ranged from 0.003 to 0.075 microM in monocyte/macrophage cultures. The EC50 values of amprenavir against HIV-2 isolates grown in PBMCs were higher than those for HIV-1 isolates, and ranged from 0.003 to 0.11 microM. The anti-HIV-1 activity of amprenavir was not antagonistic in combination with the nucleoside reverse transcriptase inhibitors (NRTIs); abacavir, didanosine, lamivudine, stavudine, tenofovir, and zidovudine; the non-nucleoside reverse transcriptase inhibitors (NNRTIs) delavirdine, efavirenz, and nevirapine; the protease inhibitors (PIs) atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir; and the gp41 fusion inhibitor enfuvirtide. These drug combinations have not been adequately studied in humans. Resistance. HIV-1 isolates with decreased susceptibility to amprenavir have been selected in cell culture and obtained from subjects treated with fosamprenavir. Genotypic analysis of isolates from treatment-naive subjects failing amprenavir-containing regimens showed substitutions in the HIV-1 protease resulting in amino acid substitutions primarily at positions V32I, M46I/L, I47V, I50V, I54L/M, and I84V, as well as substitutions in the p7/p1 and p1/p6 Gag and Gag-Pol polyprotein precursor cleavage sites. Some of these amprenavir resistance-associated substitutions have also been detected in HIV-1 isolates from antiretroviral-naive subjects treated with fosamprenavir. Of the 488 antiretroviral-naive subjects treated with fosamprenavir 1,400 mg twice daily or fosamprenavir 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, isolates from 61 subjects (29 receiving fosamprenavir and 32 receiving fosamprenavir/ritonavir) with virologic failure (plasma HIV-1 RNA greater than 1,000 copies per mL on occasions on or after Week 12) were genotyped. Isolates from of the 29 antiretroviral-naive subjects (17%) receiving fosamprenavir without ritonavir in Trial APV30001 had evidence of genotypic resistance to amprenavir: I54L/M (n 2), I54L L33F (n 1), V32I I47V (n 1), and M46I I47V (n 1). No amprenavir resistance-associated substitutions were detected in isolates from antiretroviral-naive subjects treated with fosamprenavir/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from virologic failure subject receiving fosamprenavir/ritonavir once daily at Week 160 (HIV-1 RNA greater than 500 copies per mL). Upon retrospective analysis of stored samples using an ultrasensitive assay, these resistant substitutions were traced back to Week 84 (76 weeks prior to clinical virologic failure). Cross-Resistance. Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. An association between virologic response at 48 weeks (HIV-1 RNA level less than 400 copies per mL) and protease inhibitor-resistance substitutions detected in baseline HIV-1 isolates from protease inhibitor-experienced subjects receiving fosamprenavir/ritonavir twice daily (n 88), or lopinavir/ritonavir twice daily (n 85) in Trial APV30003 is shown in Table 14. The majority of subjects had previously received either one (47%) or protease inhibitors (36%), most commonly nelfinavir (57%) and indinavir (53%). Out of 102 subjects with baseline phenotypes receiving twice-daily fosamprenavir/ritonavir, 54% (n 55) had resistance to at least one protease inhibitor, with 98% (n 54) of those having resistance to nelfinavir. Out of 97 subjects with baseline phenotypes in the lopinavir/ritonavir arm, 60% (n 58) had resistance to at least one protease inhibitor, with 97% (n 56) of those having resistance to nelfinavir. Table 14. Responders at Trial Week 48 by Presence of Baseline Protease Inhibitor Resistance-Associated SubstitutionsResults should be interpreted with caution because the subgroups were small. Protease InhibitorResistance-Associated SubstitutionsMost subjects had greater than protease inhibitor resistance-associated substitution at baseline.Fosamprenavir/Ritonavir Twice Daily(n 88)Lopinavir/Ritonavir Twice Daily(n 85)D30N 21/2295%17/1989%N88D/S 20/2291%12/12100%L90M 16/3152%17/2959%M46I/L 11/2250%12/2450%V82A/F/T/S 2/922%6/1735%I54V 2/1118%6/1155%I84V 1/617%2/540%The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects responding to fosamprenavir/ritonavir twice daily had median shift in susceptibility to amprenavir relative to standard wild-type reference strain of 0.7 (range: 0.1 to 5.4, = 62), and baseline isolates from individuals failing therapy had median shift in susceptibility of 1.9 (range: 0.2 to 14, = 29). Because this was select patient population, these data do not constitute definitive clinical susceptibility break points. Additional data are needed to determine clinically relevant break points for fosamprenavir. Isolates from 15 of the 20 subjects receiving twice-daily fosamprenavir/ritonavir up to Week 48 and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance-associated substitutions were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M, and I84V. Isolates from of the 16 subjects continuing to receive twice-daily fosamprenavir/ritonavir up to Week 96 who experienced virologic failure underwent genotypic analysis. Isolates from subjects contained amprenavir resistance-associated substitutions: V32I, M46I, and I47V in isolate and I84V in the other.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Fosamprenavir Calcium Tablets(fos am pren vir kal see um)What is the most important information should know about fosamprenavir calcium tabletsFosamprenavir calcium tablets can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with fosamprenavir calcium tablets. See the section Who should not take fosamprenavir calcium tablets Fosamprenavir calcium tablets can cause serious side effects, including:oSevere skin reactions. Fosamprenavir calcium tablets may cause severe or life-threatening skin reactions or rash.If you get rash with any of the following symptoms, stop taking fosamprenavir calcium tablets and call your healthcare provider or get medical help right away: ohives or sores in your mouth, or your skin blisters and peelsotrouble swallowing or breathingoswelling of your face, eyes, lips, tongue, or throatFor more information about side effects, see What are the possible side effects of fosamprenavir calcium tabletsWhat are fosamprenavir calcium tabletsFosamprenavir calcium tablets are prescription medicine that is used together with other antiretroviral medicines to treat human immunodeficiency virus (HIV-1) infection.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).It is not known if fosamprenavir is safe and effective in children younger than weeks of age.Do not take fosamprenavir calcium tablets if you:oare allergic to amprenavir, fosamprenavir calcium, or any of the ingredients in fosamprenavir calcium tablets. See the end of this leaflet for complete list of ingredients in fosamprenavir calcium tablets.otake any of the following medicines:oalfuzosinorifampinoergot including:dihydroergotamine mesylateergonovineergotamine tartratemethylergonovineocisaprideoSt. Johns wort (Hypericum perforatum)olomitapideolovastatinosimvastatinopimozideodelavirdine mesylateosildenafil (REVATIO), for treatment of pulmonary arterial hypertensionotriazolamomidazolam, when taken by mouthSerious problems can happen if you or your child take any of the medicines listed above with fosamprenavir calcium tablets.If you are taking fosamprenavir calcium tablets with ritonavir, do not take the following medicines: oflecainideopropafenoneolurasidoneBefore taking fosamprenavir calcium tablets, tell your healthcare provider about all of your medical conditions, including if you:oare allergic to medicines that contain sulfa.ohave or have had liver problems, including hepatitis or virus infection.ohave kidney problems.ohave high blood sugar (diabetes).ohave hemophilia.ohave high cholesterol.oare pregnant or plan to become pregnant. It is not known if fosamprenavir calcium tablets will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant during treatment with fosamprenavir calcium tablets.oFosamprenavir calcium tablets may reduce how well hormonal contraceptives (birth control pills) work. Females who may become pregnant should use different form of birth control or an additional barrier method of birth control during treatment with fosamprenavir calcium tablets.Pregnancy Registry. There is pregnancy registry for women who take fosamprenavir calcium tablets during pregnancy. The purpose of the 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.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take fosamprenavir calcium tablets.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oIt is not known if fosamprenavir can pass to your baby in your breast milk.oTalk with 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, vitamins, and herbal supplements. Some medicines interact with fosamprenavir calcium tablets. Keep list of your medicines to show your healthcare provider and pharmacist. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with fosamprenavir calcium tablets.oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take fosamprenavir calcium tablets with other medicines.How should take fosamprenavir calcium tabletsoTake fosamprenavir calcium tablets exactly as your healthcare provider tells you to take them.oIf you miss dose of fosamprenavir calcium tablets, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take.oStay under the care of healthcare provider during treatment with fosamprenavir calcium tablets.oIf your child is taking fosamprenavir calcium tablets, your childs healthcare provider will decide the right dose based on your childs weight.oFosamprenavir calcium tablets may be taken with or without food.oDo not run out of fosamprenavir calcium tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.oIf you take too many fosamprenavir calcium tablets, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of fosamprenavir calcium tabletsFosamprenavir calcium tablets may cause serious side effects including:oSee What is the most important information should know about fosamprenavir calcium tabletsoLiver problems. Your healthcare provider should do blood tests before and during your treatment with fosamprenavir calcium tablets to check your liver function. Some people with liver problems, including hepatitis or C, may have an increased risk of developing worsening liver problems during treatment with fosamprenavir calcium tablets.oDiabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors, including fosamprenavir calcium tablets, 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 during treatment with fosamprenavir calcium tablets.oChanges 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. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.oIncrease in body fat. An increase in body fat can happen in people who take protease inhibitors, including fosamprenavir calcium tablets. The exact cause and long-term health effects of these conditions are not known.oChanges in blood tests. Some people have changes in blood tests while taking fosamprenavir calcium tablets. These include an increase in liver function tests, blood fat levels (cholesterol and triglycerides) and decrease in red blood cells. Your healthcare provider should do regular blood tests before and during your treatment with fosamprenavir calcium tablets.oIncreased bleeding problems in some people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors, including fosamprenavir calcium tablets.oKidney stones. Some people have developed kidney stones during treatment with fosamprenavir calcium tablets. Tell your healthcare provider right away if you develop any of the following signs or symptoms of kidney stones:opain in your sideoblood in your urineopain when you urinateThe most common side effects of fosamprenavir calcium tablets in adults include:onauseaovomitingorashodiarrheaoheadacheThe most common side effects of fosamprenavir in children include vomiting and decrease in white blood cells.These are not all the possible side effects of fosamprenavir calcium tablets.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store fosamprenavir calcium tabletsoStore fosamprenavir calcium tablets at room temperature between 20 to 25C (68 to 77F).oKeep the bottle of fosamprenavir calcium tablets tightly closed.oFosamprenavir calcium tablets come in child-resistant package.Keep fosamprenavir calcium tablets and all medicines out of the reach of children.General information about the safe and effective use of fosamprenavir calcium tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use fosamprenavir calcium tablets for condition for which they were not prescribed. Do not give fosamprenavir calcium tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your pharmacist or healthcare provider for information about fosamprenavir calcium tablets that is written for health professionals.What are the ingredients in fosamprenavir calcium tabletsActive ingredient: fosamprenavir calciumInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, silicified microcrystalline cellulose, titanium dioxide and triacetin.Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited,Hyderabad -- 500 096, IndiaThe brand names listed are trademarks of their respective owners.For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India75079336Revised: 4/2021MX:FOSM:R7. oSevere skin reactions. Fosamprenavir calcium tablets may cause severe or life-threatening skin reactions or rash.. ohives or sores in your mouth, or your skin blisters and peelsotrouble swallowing or breathing. ohives or sores in your mouth, or your skin blisters and peels. otrouble swallowing or breathing. oswelling of your face, eyes, lips, tongue, or throat. oare allergic to amprenavir, fosamprenavir calcium, or any of the ingredients in fosamprenavir calcium tablets. See the end of this leaflet for complete list of ingredients in fosamprenavir calcium tablets.. otake any of the following medicines:oalfuzosinorifampinoergot including:dihydroergotamine mesylateergonovineergotamine tartratemethylergonovineocisaprideoSt. Johns wort (Hypericum perforatum)olomitapideolovastatinosimvastatinopimozideodelavirdine mesylateosildenafil (REVATIO), for treatment of pulmonary arterial hypertensionotriazolamomidazolam, when taken by mouth. oalfuzosin. orifampin. oergot including:dihydroergotamine mesylateergonovineergotamine tartratemethylergonovine. dihydroergotamine mesylate. ergonovine. ergotamine tartrate. methylergonovine. ocisapride. oSt. Johns wort (Hypericum perforatum). olomitapide. olovastatin. osimvastatin. opimozide. odelavirdine mesylate. osildenafil (REVATIO), for treatment of pulmonary arterial hypertension. otriazolam. omidazolam, when taken by mouth. oflecainideopropafenoneolurasidone. oflecainide. opropafenone. olurasidone. oare allergic to medicines that contain sulfa.. ohave or have had liver problems, including hepatitis or virus infection.. ohave kidney problems.. ohave high blood sugar (diabetes).. ohave hemophilia.. ohave high cholesterol.. oare pregnant or plan to become pregnant. It is not known if fosamprenavir calcium tablets will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant during treatment with fosamprenavir calcium tablets.oFosamprenavir calcium tablets may reduce how well hormonal contraceptives (birth control pills) work. Females who may become pregnant should use different form of birth control or an additional barrier method of birth control during treatment with fosamprenavir calcium tablets.. oFosamprenavir calcium tablets may reduce how well hormonal contraceptives (birth control pills) work. Females who may become pregnant should use different form of birth control or an additional barrier method of birth control during treatment with fosamprenavir calcium tablets.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take fosamprenavir calcium tablets.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oIt is not known if fosamprenavir can pass to your baby in your breast milk.oTalk with your healthcare provider about the best way to feed your baby.. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. oIt is not known if fosamprenavir can pass to your baby in your breast milk.. oTalk with your healthcare provider about the best way to feed your baby.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with fosamprenavir calcium tablets.. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take fosamprenavir calcium tablets with other medicines.. oTake fosamprenavir calcium tablets exactly as your healthcare provider tells you to take them.. oIf you miss dose of fosamprenavir calcium tablets, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take.. oStay under the care of healthcare provider during treatment with fosamprenavir calcium tablets.. oIf your child is taking fosamprenavir calcium tablets, your childs healthcare provider will decide the right dose based on your childs weight.. oFosamprenavir calcium tablets may be taken with or without food.. oDo not run out of fosamprenavir calcium tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.. oIf you take too many fosamprenavir calcium tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about fosamprenavir calcium tablets. oLiver problems. Your healthcare provider should do blood tests before and during your treatment with fosamprenavir calcium tablets to check your liver function. Some people with liver problems, including hepatitis or C, may have an increased risk of developing worsening liver problems during treatment with fosamprenavir calcium tablets.. oDiabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors, including fosamprenavir calcium tablets, 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 during treatment with fosamprenavir calcium tablets.. oChanges 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. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.. oIncrease in body fat. An increase in body fat can happen in people who take protease inhibitors, including fosamprenavir calcium tablets. The exact cause and long-term health effects of these conditions are not known.. oChanges in blood tests. Some people have changes in blood tests while taking fosamprenavir calcium tablets. These include an increase in liver function tests, blood fat levels (cholesterol and triglycerides) and decrease in red blood cells. Your healthcare provider should do regular blood tests before and during your treatment with fosamprenavir calcium tablets.. oIncreased bleeding problems in some people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors, including fosamprenavir calcium tablets.. oKidney stones. Some people have developed kidney stones during treatment with fosamprenavir calcium tablets. Tell your healthcare provider right away if you develop any of the following signs or symptoms of kidney stones:opain in your sideoblood in your urineopain when you urinate. opain in your side. oblood in your urine. opain when you urinate. onausea. ovomiting. orash. odiarrhea. oheadache. oStore fosamprenavir calcium tablets at room temperature between 20 to 25C (68 to 77F).. oKeep the bottle of fosamprenavir calcium tablets tightly closed.. oFosamprenavir calcium tablets come in child-resistant package.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding is not recommended due to potential for HIV transmission. (8.2). 8.1 Pregnancy. Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk Summary. Limited data are available for use of fosamprenavir in pregnancy. Fosamprenavir 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data). There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir. In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD.In the rat pre- and postnatal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately times the exposure in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir (see Data). Clinical Considerations. Virologic Monitoring During Pregnancy and the Postpartum Period Based on limited data on the use of fosamprenavir during pregnancy, no dosage adjustments are required for pregnant patients who are already on stable twice-daily regimen of fosamprenavir 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. In clinical trial of 10 HIV-1-infected pregnant women treated with fosamprenvir 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period. Therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Data, Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Pregnancy data with other dosage regimens of fosamprenavir (with or without ritonavir) are not available.. Data. Human Data Fosamprenavir 700 mg taken with ritonavir 100 mg twice daily in combination with background regimen was evaluated in clinical trial of 10 HIV-1-infected pregnant women during the second and third trimesters and postpartum. Subjects initiated fosamprenavir/ritonavir during pregnancy at median of 19 weeks gestation; had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation. Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n 6) or third trimester (n 9) and postpartum (n 9). Pregnancy outcomes were available for all 10 subjects, among which twin pregnancy was included. Compared to the postpartum period, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n 7) was 0.27 (0.24 to 0.30) [see Clinical Pharmacology (12.3)]. At delivery, subjects had HIV-1 viral load less than 50 copies/mL, and subject had viral load of 111 copies/mL. All 11 infants born had test results that were negative for HIV-1 at the time of delivery and through 12 months postpartum. There were no new safety findings compared with the known safety profile of fosamprenavir/ritonavir in HIV-1-infected adults.Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens, there were birth defects reported in 109 first trimester exposures and birth defects reported in 36 second and third trimester exposures. The background rate for major birth defects is 2.7% in U.S. reference population of the MACDP. Prospective reports from the APR of overall major birth defects in pregnancies exposed to fosamprenavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease.. Animal Data Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on Gestation Days to 17 and Days to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC0-24 h) approximately times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir. However, increased incidence of abortion was observed in rabbits administered maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on Gestation Days to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD.In the rat pre- and postnatal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on Gestation Day to Lactation/Postpartum Day 20. Fosamprenavir caused reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed. Systemic exposure (AUC0-24 h) to amprenavir in rats was approximately times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.. 8.2 Lactation Risk Summary. The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.There is no information available on the presence of amprenavir in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. When administered to lactating rats, amprenavir was present in milk (see Data). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving fosamprenavir.. Data. Amprenavir was excreted into the milk of lactating rats following single dose of amprenavir (100 mg per kg); maximal milk concentration was achieved hours post-administration at milk concentration approximately 1.2 times that of maternal plasma concentrations.. 8.3 Females and Males of Reproductive Potential. Contraception. Use of fosamprenavir may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.2)]. 8.4 Pediatric Use. The safety, pharmacokinetic profile, and virologic and immunologic responses of fosamprenavir with and without ritonavir were evaluated in protease inhibitor-naive and -experienced HIV-1-infected pediatric subjects aged at least weeks to younger than 18 years and weighing at least kg in open-label trials [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.3)]. Treatment with fosamprenavir is not recommended in protease inhibitor-experienced pediatric patients younger than months. The pharmacokinetics, safety, tolerability, and efficacy of fosamprenavir in pediatric patients younger than weeks have not been established [see Clinical Pharmacology (12.3)]. Available pharmacokinetic and clinical data do not support once-daily dosing of fosamprenavir alone or in combination with ritonavir for any pediatrics or twice-daily dosing without ritonavir in pediatric patients younger than years [see Clinical Pharmacology (12.3), Clinical Studies (14.3)]. See Dosage and Administration (2.3) for dosing recommendations for pediatric patients. 8.5 Geriatric Use. Clinical studies of fosamprenavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adults. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Amprenavir is principally metabolized by the liver; therefore, caution should be exercised when administering fosamprenavir to patients with hepatic impairment because amprenavir concentrations may be increased [see Clinical Pharmacology (12.3)]. Patients with impaired hepatic function receiving fosamprenavir with or without concurrent ritonavir require dose reduction [see Dosage and Administration (2.4)]. There is no data to support dosing recommendations for pediatric subjects with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oThe concomitant use of fosamprenavir with ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.3) oFosamprenavir should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) oFosamprenavir should be used with caution in patients with known sulfonamide allergy. (5.3) oUse of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis or are at increased risk of transaminase elevations. (5.4) oPatients receiving fosamprenavir may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.5), immune reconstitution syndrome (5.6), increase of body fat (5.7), and elevated triglyceride and cholesterol concentrations (5.8). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. oAcute hemolytic anemia has been reported with amprenavir. (5.9) oHemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.10) oNephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. (5.11) oThe concomitant use of fosamprenavir with ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.3) oFosamprenavir should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) oFosamprenavir should be used with caution in patients with known sulfonamide allergy. (5.3) oUse of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis or are at increased risk of transaminase elevations. (5.4) oPatients receiving fosamprenavir may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.5), immune reconstitution syndrome (5.6), increase of body fat (5.7), and elevated triglyceride and cholesterol concentrations (5.8). Monitor cholesterol and triglycerides prior to therapy and periodically thereafter. oAcute hemolytic anemia has been reported with amprenavir. (5.9) oHemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.10) oNephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. (5.11) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of fosamprenavir/ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir/ritonavir may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of fosamprenavir/ritonavir, respectively. These interactions may lead to: oclinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. oclinically significant adverse reactions from greater exposures of fosamprenavir/ritonavir. oloss of therapeutic effect of fosamprenavir/ritonavir and possible development of resistance.See Table 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 therapy with fosamprenavir/ritonavir; review concomitant medications during therapy with fosamprenavir/ritonavir; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4), Drug Interactions (7)].. oclinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. oclinically significant adverse reactions from greater exposures of fosamprenavir/ritonavir. oloss of therapeutic effect of fosamprenavir/ritonavir and possible development of resistance.. 5.2 Skin Reactions Severe and life-threatening skin reactions, including case of Stevens-Johnson syndrome among 700 subjects treated with fosamprenavir in clinical trials. Treatment with fosamprenavir should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms [see Adverse Reactions (6)]. 5.3 Sulfa Allergy Fosamprenavir should be used with caution in patients with known sulfonamide allergy. Fosamprenavir contains sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown. In clinical trial of fosamprenavir used as the sole protease inhibitor, rash occurred in of 10 subjects (20%) with history of sulfonamide allergy compared with 42 of 126 subjects (33%) with no history of sulfonamide allergy. In clinical trials of fosamprenavir plus low-dose ritonavir, rash occurred in of 50 subjects (16%) with history of sulfonamide allergy compared with 50 of 412 subjects (12%) with no history of sulfonamide allergy. 5.4 Hepatic Toxicity Use of fosamprenavir with ritonavir at higher-than-recommended dosages may result in transaminase elevations and should not be used [see Dosage and Administration (2), Overdosage (10)]. Patients with underlying hepatitis or or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy with fosamprenavir and patients should be monitored closely during treatment. 5.5 Diabetes/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1- infected patients receiving protease inhibitor 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 protease inhibitor 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 protease inhibitor therapy and these events have not been established. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including fosamprenavir. 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, and Guillain-Barre syndrome) 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 treatment.. 5.7 Increase in Body Fat. Increase of body fat has been observed in patients receiving protease inhibitors, including fosamprenavir. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.8 Lipid Elevations Treatment with fosamprenavir plus ritonavir has resulted in increases in the concentration of triglycerides and cholesterol [see Adverse Reactions (6)]. Triglyceride and cholesterol testing should be performed prior to initiating therapy with fosamprenavir and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate [see Drug Interactions (7)]. 5.9 Hemolytic Anemia Acute hemolytic anemia has been reported in patient treated with amprenavir. 5.10 Patients with Hemophilia There have been reports of spontaneous bleeding in patients with hemophilia and treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. causal relationship between protease inhibitor therapy and these episodes has not been established. 5.11 Nephrolithiasis Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-1- infected patients receiving fosamprenavir. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered. 5.12 Resistance/Cross-Resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored, it is unknown what effect therapy with fosamprenavir will have on the activity of subsequently administered protease inhibitors. Fosamprenavir has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (14.2)].

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oTherapy-Naive Adults: Fosamprenavir 1,400 mg twice daily; fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) oProtease Inhibitor-Experienced Adults: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) oPregnant Patients: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in women who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). (2.2)oPediatric Patients (aged at least weeks to 18 years): Dosage should be calculated based on body weight (kg) and should not exceed adult dose. (2.3) oHepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. (2.4) Dosing Considerations oFosamprenavir calcium tablets may be taken with or without food. (2.1). oTherapy-Naive Adults: Fosamprenavir 1,400 mg twice daily; fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) oProtease Inhibitor-Experienced Adults: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2) oPregnant Patients: Fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in women who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). (2.2). oPediatric Patients (aged at least weeks to 18 years): Dosage should be calculated based on body weight (kg) and should not exceed adult dose. (2.3) oHepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. (2.4) oFosamprenavir calcium tablets may be taken with or without food. (2.1). 2.1General Dosing Information Fosamprenavir calcium tablets may be taken with or without food. Higher-than-approved dose combinations of fosamprenavir plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)]. When fosamprenavir is used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir. 2.2 Adults Therapy-Naive Adults oFosamprenavir 1,400 mg twice daily (without ritonavir). oFosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily. oFosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily. oDosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)]. oFosamprenavir 1,400 mg twice daily (without ritonavir). oFosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily. oFosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily. oDosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. oDosing of fosamprenavir 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)]. oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)]. Protease Inhibitor-Experienced Adults oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Pregnancy. oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily.oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Use in Specific Populations (8.1), Clinical Pharmacology (12.3)]. Data regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available.. oFosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily.oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Use in Specific Populations (8.1), Clinical Pharmacology (12.3)]. Data regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available.. oDosing of fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of amprenavir were observed during pregnancy; therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Use in Specific Populations (8.1), Clinical Pharmacology (12.3)]. Data regarding use of other regimens of fosamprenavir (with or without ritonavir) in pregnancy are not available.. 2.3 Pediatric Patients (Aged at Least Weeks to 18 Years) The recommended dosage of fosamprenavir in patients aged at least weeks to 18 years should be calculated based on body weight (kg) and should not exceed the recommended adult dose (Table 1). Table 1. Twice-Daily Dosage Regimens by Weight for Protease Inhibitor-Naive Pediatric Patients (Aged Weeks and Older) and for Protease Inhibitor-Experienced Pediatric Patients (Aged Months and Older) Using Fosamprenavir Calcium Oral Suspension with Concurrent RitonavirWeightTwice-Daily Dosage Regimen< 11 kgFosamprenavir 45 mg/kg plus ritonavir mg/kgWhen dosing with ritonavir, do not exceed the adult dose of fosamprenavir 700 mg/ritonavir 100 mg twice-daily dose. 11 kg < 15 kgFosamprenavir 30 mg/kg plus ritonavir mg/kg 15 kg < 20 kgFosamprenavir 23 mg/kg plus ritonavir mg/kg >= 20 kgFosamprenavir 18 mg/kg plus ritonavir mg/kg Alternatively, protease inhibitor-naive children aged years and older can be administered fosamprenavir (without ritonavir) 30 mg per kg twice daily.Fosamprenavir should only be administered to infants born at 38 weeks gestation or greater and who have attained postnatal age of 28 days.For pediatric patients, pharmacokinetic and clinical data:odo not support once-daily dosing of fosamprenavir alone or in combination with ritonavir [see Clinical Studies (14.3)].odo not support administration of fosamprenavir alone or in combination with ritonavir for protease inhibitor-experienced children younger than months [see Clinical Pharmacology (12.3)].odo not support twice-daily dosing of fosamprenavir without ritonavir in pediatric patients younger than years [see Clinical Pharmacology (12.3)].. odo not support once-daily dosing of fosamprenavir alone or in combination with ritonavir [see Clinical Studies (14.3)].. odo not support administration of fosamprenavir alone or in combination with ritonavir for protease inhibitor-experienced children younger than months [see Clinical Pharmacology (12.3)].. odo not support twice-daily dosing of fosamprenavir without ritonavir in pediatric patients younger than years [see Clinical Pharmacology (12.3)].. Other Dosing Considerations oWhen administered without ritonavir, the adult regimen of fosamprenavir calcium tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg. oWhen administered in combination with ritonavir, fosamprenavir calcium tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg. oWhen administered without ritonavir, the adult regimen of fosamprenavir calcium tablets 1,400 mg twice daily may be used for pediatric patients weighing at least 47 kg. oWhen administered in combination with ritonavir, fosamprenavir calcium tablets may be used for pediatric patients weighing at least 39 kg; ritonavir capsules may be used for pediatric patients weighing at least 33 kg. 2.4 Patients with Hepatic Impairment See Clinical Pharmacology (12.3). Mild Hepatic Impairment (Child-Pugh Score Ranging from to 6). Fosamprenavir should be used with caution at reduced dosage of 700 mg twice daily without ritonavir (therapy-naive) or 700 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). Moderate Hepatic Impairment (Child-Pugh Score Ranging from to 9). Fosamprenavir should be used with caution at reduced dosage of 700 mg twice daily without ritonavir (therapy-naive), or 450 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). Severe Hepatic Impairment (Child-Pugh Score Ranging from 10 to 15). Fosamprenavir should be used with caution at reduced dosage of 350 mg twice daily without ritonavir (therapy-naive) or 300 mg twice daily plus ritonavir 100 mg once daily (therapy-naive or protease inhibitor-experienced). There are no data to support dosing recommendations for pediatric patients with hepatic impairment.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oCoadministration of fosamprenavir with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3) oCoadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3) oCoadministration of fosamprenavir or fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7)oCoadministration of fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. (7). oCoadministration of fosamprenavir with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3) oCoadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3) oCoadministration of fosamprenavir or fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7). oCoadministration of fosamprenavir and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. (7). 7.1 Cytochrome P450 Inhibitors and Inducers Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4. Amprenavir is metabolized by CYP3A4. Coadministration of fosamprenavir and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects. The potential for drug interactions with fosamprenavir changes when fosamprenavir is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when fosamprenavir is coadministered with ritonavir. Because ritonavir is CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir plus ritonavir. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other enzymes, including glucuronosyl transferase.There are other agents that may result in serious and/or life-threatening drug interactions [see Contraindications (4)]. 7.2 Established and Other Potentially Significant Drug Interactions If fosamprenavir is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions [see Contraindications (4), Clinical Pharmacology (12.3)].Table provides listing of established or potentially clinically significant drug interactions. Information in the table applies to fosamprenavir with or without ritonavir, unless otherwise indicated.Table 6. Established and Other Potentially Significant Drug InteractionsConcomitant Drug Class: Drug NameEffect on Concentration of Amprenavir or Concomitant DrugClinical CommentHCV/HIV-Antiviral AgentsHCV protease inhibitor:BoceprevirFosamprenavir: Amprenavir (predicted)<-> or Boceprevir (predicted) Fosamprenavir/ritonavir: Amprenavir (predicted) Boceprevir (predicted)Coadministration of fosamprenavir or fosamprenavir/ritonavir and boceprevir is not recommended.HCV protease inhibitor:SimeprevirFosamprenavir:<-> Amprenavir (predicted) or Simeprevir (predicted)Fosamprenavir/ritonavir: <-> Amprenavir (predicted) Simeprevir (predicted)Coadministration of fosamprenavir or fosamprenavir/ritonavir and simeprevir is not recommended.HCV protease inhibitor:Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)Fosamprenavir: Amprenavir (predicted) or <-> Paritaprevir (predicted)Fosamprenavir/ritonavir: or <-> Amprenavir (predicted) Paritaprevir (predicted)Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/dasabuvir. Coadministration of fosamprenavir/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.Non-nucleoside reverse transcriptase inhibitor:DelavirdineSee Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction. Fosamprenavir: Amprenavir Delavirdine Fosamprenavir/ritonavir: Amprenavir DelavirdineCoadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine [see Contraindications (4)].Non-nucleoside reverse transcriptase inhibitor:Efavirenz Fosamprenavir: Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.Fosamprenavir/ritonavir: AmprenavirAn additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.Non-nucleoside reverse transcriptase inhibitor:Nevirapine Fosamprenavir: Amprenavir NevirapineCoadministration of nevirapine and fosamprenavir without ritonavir is not recommended.Fosamprenavir/ritonavir: Amprenavir NevirapineNo dosage adjustment required when nevirapine is administered with fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once-daily regimen has not been studied.HIV protease inhibitor:Atazanavir Fosamprenavir:Interaction has not been evaluated. Fosamprenavir/ ritonavir: Atazanavir<-> Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Indinavir, nelfinavir Fosamprenavir: Amprenavir Effect on indinavir and nelfinavir is not well established. Fosamprenavir/ ritonavir: Interaction has not been evaluated. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitors: Lopinavir/ritonavir Amprenavir Lopinavir An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV protease inhibitor:Saquinavir Fosamprenavir: Amprenavir Effect on saquinavir is not well established. Fosamprenavir/ ritonavir: Interaction has not been evaluated. Appropriate doses of the combination with respect to safety and efficacy have not been established. HIV integrase inhibitor:Raltegravir Fosamprenavir: Amprenavir Raltegravir Fosamprenavir/ ritonavir: Amprenavir Raltegravir Appropriate doses of the combination with respect to safety and efficacy have not been established.HIV integrase inhibitor:DolutegravirFosamprenavir/ritonavir: DolutegravirThe recommended dose of dolutegravir is 50 mg twice daily when coadministered with fosamprenavir/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.HIV CCR5 co-receptor antagonist: Maraviroc Fosamprenavir/ritonavir: Amprenavir MaravirocNo dosage adjustment required for fosamprenavir/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with fosamprenavir/ritonavir. Fosamprenavir should be given with ritonavir when coadministered with maraviroc.Other AgentsAlpha 1-adrenoreceptorantagonist:Alfuzosin AlfuzosinCoadministration is contraindicated dueto potential hypotension [see Contraindications (4)].Antacid:MAALOX TC(R) AmprenavirUse with caution when administered atthe same time. Fosamprenavir may be lesseffective due to decreased amprenavirplasma concentrations. Staggered coadministration of antacidsand fosamprenavir has not been evaluated.Antiarrhythmics:Amiodarone, disopyramide, lidocaine (systemic), and quinidine Antiarrhythmics Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.Antiarrhythmics:Flecainide, propafenone AntiarrhythmicsCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir is co-prescribed with ritonavir [see Contraindications (4)].Anticoagulant: WarfarinConcentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.Anticonvulsants: Carbamazepine, phenobarbital, phenytoinFosamprenavir: AmprenavirUse with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Phenytoin Fosamprenavir/ritonavir: Amprenavir PhenytoinPlasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in fosamprenavir/ritonavir dose is recommended.Antidepressant: Paroxetine, trazodone ParoxetineAny paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). TrazodoneAdverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with CYP3A4 inhibitor such as fosamprenavir, the combination should be used with caution and lower dose of trazodone should be considered.Antifungals: Ketoconazole, itraconazole Ketoconazole Itraconazole Increase monitoring for adverse events. Fosamprenavir: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Fosamprenavir/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.Anti-gout:Colchicine Colchicine Patients with renal or hepatic impairment should not be given colchicine with fosamprenavir/ritonavir. Fosamprenavir/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) 1 dose, followed by 0.3 mg (half tablet) hour later. Dose to be repeated no earlier than days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg once day. If the original regimen was 0.6 mg once day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice day). Fosamprenavir and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) 1 dose. Dose to be repeated no earlier than days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg twice day or 0.6 mg once day. If the original regimen was 0.6 mg once day, the regimen should be adjusted to 0.3 mg once day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice day).Antimycobacterial: Rifabutin Rifabutin and rifabutin metabolite complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. Fosamprenavir: dosage reduction of rifabutin by at least half the recommended dose is required. Fosamprenavir/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or times per week). Antimycobacterial: Rifampina AmprenavirCoadministration is contraindicated as it may lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors [see Contraindications (4)].Antineoplastics:Dasatinib, nilotinib,ibrutinib, vinblastine,everolimus AntineoplasticsFosamprenavir or fosamprenavir/ritonavir may increase plasma concentrations of antineoplastics metabolized by CYP3A, potentially increasing the risk of adverse events typically associated with these medications. In case of coadministration, please refer to relevant prescribing information for these medications.Antipsychotics: Lurasidone LurasidoneFosamprenavir: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.Fosamprenavir/ritonavir: Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)].Pimozide PimozideCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].Quetiapine QuetiapineFosamprenavir/ritonavir:Initiation of fosamprenavir with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.Initiation of quetiapine in patients taking fosamprenavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.Benzodiazepines:Alprazolam, clorazepate, diazepam, flurazepam Benzodiazepines Clinical significance is unknown. decrease in benzodiazepine dose may be needed. Calcium channel blockers:Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine Calcium channel blockers Use with caution. Clinical monitoring of patients is recommended. Corticosteroid:Dexamethasone Amprenavir Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations. Endothelin-receptor antagonist:Bosentan Bosentan Coadministration of bosentan in patients on fosamprenavir:In patients who have been receiving fosamprenavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of fosamprenavir in patients on bosentan:Discontinue use of bosentan at least 36 hours prior to initiation of fosamprenavir. After at least 10 days following the initiation of fosamprenavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine,methylergonovine Ergot derivativesCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].GI motility agent: Cisapride CisaprideCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].Herbal product:St. Johns wort(Hypericum perforatum) AmprenavirCoadministration is contraindicated as it may lead to loss of virologic response and possible resistance to fosamprenavir or to the class of protease inhibitors [see Contraindications (4)].Histamine H2-receptorantagonists:Cimetidine, famotidine, nizatidine, ranitidine Fosamprenavir: Amprenavir Fosamprenavir/ ritonavir: Interaction not evaluated Use with caution. Fosamprenavir may be less effective due to decreased amprenavir plasma concentrations. Immunosuppressants:Cyclosporine, tacrolimus, sirolimus ImmunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents.Inhaled beta-agonist:Salmeterol Salmeterol Concurrent administration of salmeterol with fosamprenavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.Inhaled/nasal steroid:FluticasoneFosamprenavir: Fluticasone Fosamprenavir/ritonavir: FluticasoneUse with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and fosamprenavir/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.Lipid Modifying Agents:HMG-CoA reductase inhibitors:Atorvastatina AtorvastatinTitrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.Lovastatin, simvastatin Lovastatin SimvastatinCoadministration with lovastatin orsimvastatin is contraindicated due topotential for serious reactions such as riskof myopathy including rhabdomyolysis[see Contraindications (4)].Other lipid modifying agents:Lomitapide LomitapideCoadministration with lomitapide iscontraindicated due to potential formarkedly increased transaminases.Narcotic analgesic:Methadone Methadone Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.Fentanyl FentanylCareful monitoring of therapeutic effectsand adverse effects of fentanyl (includingpotentially fatal respiratory depression) isrecommended.Oral contraceptives:Ethinyl estradiol/norethindrone Fosamprenavir: Amprenavir Ethinyl estradiolAlternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. Fosamprenavir/ritonavir: Ethinyl estradiolIncreased risk of transaminase elevations. No data are available on the use of fosamprenavir/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.PDE5 inhibitors:Sildenafil, tadalafil, vardenafil Sildenafil Tadalafil Vardenafil May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH. safe and effective dose has not been established when used with fosamprenavir. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope) [see Contraindications (4)]. oThe following dose adjustments are recommended for use of tadalafil (ADCIRCA(R)) with fosamprenavir: Coadministration of ADCIRCA in patients on fosamprenavir: In patients receiving fosamprenavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of fosamprenavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of fosamprenavir. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir. After at least one week following the initiation of fosamprenavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Fosamprenavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. Fosamprenavir/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events.Proton pump inhibitors:Esomeprazole lansoprazole, omeprazole, pantoprazole, rabeprazoleFosamprenavir:<-> Amprenavir Esomeprazole Fosamprenavir/ritonavir:<-> Amprenavir <-> EsomeprazoleProton pump inhibitors can be administered at the same time as dose of fosamprenavir with no change in plasma amprenavir concentrations.Sedative/hypnotics:Midazolam, triazolam Midazolam TriazolamCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression [see Contraindications (4)].Tricyclic antidepressants:Amitriptyline, imipramine Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants. oThe following dose adjustments are recommended for use of tadalafil (ADCIRCA(R)) with fosamprenavir: Coadministration of ADCIRCA in patients on fosamprenavir: In patients receiving fosamprenavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of fosamprenavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of fosamprenavir. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir. After at least one week following the initiation of fosamprenavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. oSevere or life-threatening skin reactions have been reported with the use of fosamprenavir [see Warnings and Precautions (5.2)]. oThe most common moderate to severe adverse reactions in clinical trials of fosamprenavir were diarrhea, rash, nausea, vomiting, and headache. oTreatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash. oSevere or life-threatening skin reactions have been reported with the use of fosamprenavir [see Warnings and Precautions (5.2)]. oThe most common moderate to severe adverse reactions in clinical trials of fosamprenavir were diarrhea, rash, nausea, vomiting, and headache. oTreatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash. oIn adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. (6.1) oVomiting and neutropenia were more frequent in pediatrics than in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oIn adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. (6.1) oVomiting and neutropenia were more frequent in pediatrics than in adults. (6.1) 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.. Adult Trials. The data for the active-controlled clinical trials described below reflect exposure of 700 HIV-1- infected subjects to fosamprenavir calcium tablets, including 599 subjects exposed to fosamprenavir for greater than 24 weeks, and 409 subjects exposed for greater than 48 weeks. The population age ranged from 17 to 72 years. Of these subjects, 26% were female, 51% white, 31% black, 16% American Hispanic, and 70% were antiretroviral-naive. Sixty-one percent received fosamprenavir 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir 1,400 mg twice daily; and 15% received fosamprenavir 700 mg twice daily plus ritonavir 100 mg twice daily. Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir are shown in Tables and 3. Each table presents adverse reactions of moderate or severe intensity in subjects treated with combination therapy for up to 48 weeks. Table 2. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult SubjectsAdverse ReactionAPV30001All subjects also received abacavir and lamivudine twice daily.APV30002Fosamprenavir1,400 mg Twice Daily(n 166)Nelfinavir1,250 mg Twice Daily(n 83)Fosamprenavir1,400 mg and Ritonavir200 mg Once Daily(n 322)Nelfinavir1,250 mg Twice Daily(n 327)Gastrointestinal Diarrhea5%18%10%18% Nausea 7%4%7%5% Vomiting 2%4%6%4% Abdominal pain 1%0%2%2%Skin Rash 8%2%3%2%General disorders Fatigue 2%1%4%2%Nervous system Headache 2%4%3%3%Table 3. Selected Moderate/Severe Clinical Adverse Reactions Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects (Trial APV30003)Adverse ReactionFosamprenavir700 mg andRitonavir 100 mg Twice DailyAll subjects also received reverse transcriptase inhibitors.(n 106)Lopinavir 400 mg andRitonavir 100 mg Twice Daily(n 103)Gastrointestinal Diarrhea 13%11% Nausea 3%9% Vomiting 3%5% Abdominal pain 1%2%Skin Rash 3%0%Nervous system Headache4%2%Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with fosamprenavir in the pivotal efficacy trials. Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus. Rash had median onset of 11 days after initiation of fosamprenavir and had median duration of 13 days. Skin rash led to discontinuation of fosamprenavir in less than 1% of subjects. In some subjects with mild or moderate rash, dosing with fosamprenavir was often continued without interruption; if interrupted, reintroduction of fosamprenavir generally did not result in rash recurrence. The percentages of subjects with Grade or laboratory abnormalities in the clinical efficacy trials of fosamprenavir are presented in Tables and 5. Table 4. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Antiretroviral-Naive Adult Subjects in Trials APV30001 and APV30002ULN Upper limit of normal.Laboratory AbnormalityAPV30001All subjects also received abacavir and lamivudine twice daily.APV30002Fosamprenavir1,400 mg Twice Daily(n 166)Nelfinavir1,250 mg Twice Daily(n 83)Fosamprenavir1,400 mg andRitonavir200 mg Once Daily(n 322)Nelfinavir1,250 mg Twice Daily(n 327)ALT (> x ULN) 6%5%8%8%AST (> x ULN) 6%6%6%7%Serum lipase (> x ULN) 8%4%6%4%TriglyceridesFasting specimens. (> 750 mg/dL) 0%1%6%2%Neutrophil count, absolute (< 750 cells/mm3)3%6%3%4%The incidence of Grade or hyperglycemia in antiretroviral-naive subjects who received fosamprenavir in the pivotal trials was less than 1%. Table 5. Grade 3/4 Laboratory Abnormalities Reported in Greater than or Equal to 2% of Protease Inhibitor-Experienced Adult Subjects in Trial APV30003ULN Upper limit of normal.Laboratory AbnormalityFosamprenavir700 mg andRitonavir 100 mg Twice Daily.All subjects also received reverse transcriptase inhibitors.(n 104)Lopinavir 400 mg andRitonavir 100 mg Twice Daily(n 103)TriglyceridesFasting specimens. (> 750 mg/dL)11%n 100 for fosamprenavir plus ritonavir, = 98 for lopinavir plus ritonavir. 6% Serum lipase (> x ULN)5%12%ALT (> x ULN)4%4%AST (> x ULN)4%2%Glucose (> 251 mg/dL)2% 2% Pediatric Trials. Fosamprenavir with and without ritonavir was studied in 237 HIV-1- infected pediatric subjects aged at least weeks to 18 years in open-label trials; APV20002, APV20003, and APV29005 [see Clinical Studies (14.3)]. Vomiting and neutropenia occurred more frequently in pediatric subjects compared with adults. Other adverse events occurred with similar frequency in pediatric subjects compared with adults. The frequency of vomiting among pediatric subjects receiving fosamprenavir twice daily with ritonavir was 20% in subjects aged at least weeks to younger than years and 36% in subjects aged to 18 years compared with 10% in adults. The frequency of vomiting among pediatric subjects receiving fosamprenavir twice daily without ritonavir was 60% in subjects aged to years compared with 16% in adults.The median duration of drug-related vomiting episodes in APV29005 was day (range: to days), in APV20003 was 16 days (range: to 38 days), and in APV20002 was days (range: to 13 days). Vomiting was treatment limiting in pediatric subjects across all trials. The incidence of Grade or neutropenia (neutrophils less than 750 cells per mm3) seen in pediatric subjects treated with fosamprenavir with and without ritonavir was higher (15%) than the incidence seen in adult subjects (3%). Grade 3/4 neutropenia occurred in 10% (5 of 51) of subjects aged at least weeks to younger than years and 16% (28 of 170) of subjects aged to 18 years. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fosamprenavir. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to fosamprenavir. Cardiac Disorders: Myocardial infarction. Metabolism and Nutrition Disorders: Hypercholesterolemia. Nervous System Disorders: Oral paresthesia. Skin and Subcutaneous Tissue Disorders: Angioedema. Urogenital: Nephrolithiasis.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Therapy-Naive Adult Trials APV30001. randomized, open-label trial evaluated treatment with fosamprenavir calcium tablets (1,400 mg twice daily) versus nelfinavir (1,250 mg twice daily) in 249 antiretroviral treatment-naive subjects. Both groups of subjects also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily). The mean age of the subjects in this trial was 37 years (range: 17 to 70 years); 69% of the subjects were male, 20% were CDC Class (AIDS), 24% were white, 32% were black, and 44% were Hispanic. At baseline, the median CD4+ cell count was 212 cells per mm3 (range: to 1,136 cells per mm3; 18% of subjects had CD4+ cell count of less than 50 cells per mm3 and 30% were in the range of 50 to less than 200 cells per mm3). Baseline median HIV-1 RNA was 4.83 log10 copies per mL (range: 1.69 to 7.41 log10 copies per mL; 45% of subjects had greater than 100,000 copies per mL). The outcomes of randomized treatment are provided in Table 15. Table 15. Outcomes of Randomized Treatment through Week 48 (APV30001)Outcome(Rebound or discontinuation failure)Fosamprenavir1,400 mg Twice Daily(n 166)Nelfinavir1,250 mg Twice Daily(n 83)ResponderSubjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5). 66% (57%)52% (42%)Virologic failure 19%32%Rebound 16%19%Never suppressed through Week 48 3%13%Clinical progression 1%1%Death 0%1%Discontinued due to adverse reactions 4%2%Discontinued due to other reasonsIncludes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons. 10%10%Treatment response by viral load strata is shown in Table 16. Table 16. Proportions of Responders through Week 48 by Screening Viral Load (APV30001)Screening Viral LoadHIV-1 RNA(copies/mL)Fosamprenavir1,400 mg Twice DailyNelfinavir1,250 mg Twice Daily< 400 copies/mLn< 400 copies/mLn<= 100,000 65%9365%46> 100,000 67%7336%37Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells per mm3 in the group receiving fosamprenavir and 216 cells per mm3 in the nelfinavir group. APV30002. randomized, open-label trial evaluated treatment with fosamprenavir calcium tablets (1,400 mg once daily) plus ritonavir (200 mg once daily) versus nelfinavir (1,250 mg twice daily) in 649 treatment-naive subjects. Both treatment groups also received abacavir (300 mg twice daily) and lamivudine (150 mg twice daily). The mean age of the subjects in this trial was 37 years (range: 18 to 69 years); 73% of the subjects were male, 22% were CDC Class C, 53% were white, 36% were black, and 8% were Hispanic. At baseline, the median CD4+ cell count was 170 cells per mm3 (range: to 1,055 cells per mm3; 20% of subjects had CD4+ cell count of less than 50 cells per mm3 and 35% were in the range of 50 to less than 200 cells per mm3). Baseline median HIV-1 RNA was 4.81 log10 copies per mL (range: 2.65 to 7.29 log10 copies per mL; 43% of subjects had greater than 100,000 copies per mL).The outcomes of randomized treatment are provided in Table 17.Table 17. Outcomes of Randomized Treatment through Week 48 (APV30002)Outcome(Rebound or discontinuation failure)Fosamprenavir1,400 mg/Ritonavir 200 mg Once Daily(n 322)Nelfinavir1,250 mg Twice Daily(n 327)ResponderSubjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (less than 50 copies per mL) through Week 48 (Roche AMPLICOR HIV-1 MONITOR Assay Version 1.5). 69% (58%)68% (55%)Virologic failure 6%16%Rebound 5%8%Never suppressed through Week 48 1%8%Death 1%0%Discontinued due to adverse reactions 9%6%Discontinued due to other reasonsIncludes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons. 15%10%Treatment response by viral load strata is shown in Table 18.Table 18. Proportions of Responders through Week 48 by Screening Viral Load (APV30002)Screening Viral LoadHIV-1 RNA(copies/mL)Fosamprenavir1,400 mg/Ritonavir 200 mg Once DailyNelfinavir1,250 mg Twice Daily< 400 copies/mLn< 400 copies/mLn<= 100,000 72%19773%194> 100,000 66%12564%133Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells per mm3 in the group receiving fosamprenavir and 207 cells per mm3 in the nelfinavir group.. 14.2 Protease Inhibitor-Experienced Adult Trials. APV30003. randomized, open-label, multicenter trial evaluated different regimens of fosamprenavir plus ritonavir (fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily or fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily) versus lopinavir/ritonavir (400 mg/100 mg twice daily) in 315 subjects who had experienced virologic failure to or prior protease inhibitor-containing regimens.The mean age of the subjects in this trial was 42 years (range: 24 to 72 years); 85% were male, 33% were CDC Class C, 67% were white, 24% were black, and 9% were Hispanic. The median CD4+ cell count at baseline was 263 cells per mm3 (range: to 1,171 cells per mm3). Baseline median plasma HIV-1 RNA level was 4.14 log10 copies per mL (range: 1.69 to 6.41 log10 copies per mL). The median durations of prior exposure to NRTIs were 257 weeks for subjects receiving fosamprenavir/ritonavir twice daily (79% had greater than or equal to prior NRTIs) and 210 weeks for subjects receiving lopinavir/ritonavir (64% had greater than or equal to prior NRTIs). The median durations of prior exposure to protease inhibitors were 149 weeks for subjects receiving fosamprenavir/ritonavir twice daily (49% received greater than or equal to prior protease inhibitors) and 130 weeks for subjects receiving lopinavir/ritonavir (40% received greater than or equal to prior protease inhibitors). The time-averaged changes in plasma HIV-1 RNA from baseline (AAUCMB) at 48 weeks (the endpoint on which the trial was powered) were -1.4 log10 copies per mL for twice-daily fosamprenavir/ritonavir and -1.67 log10 copies per mL for the lopinavir/ritonavir group. The proportions of subjects who achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL (secondary efficacy endpoint) were 58% with twice-daily fosamprenavir/ritonavir and 61% with lopinavir/ritonavir (95% CI for the difference: -16.6, 10.1). The proportions of subjects with HIV-1 RNA less than 50 copies per mL with twice-daily fosamprenavir/ritonavir and with lopinavir/ritonavir were 46% and 50%, respectively (95% CI for the difference: -18.3, 8.9). The proportions of subjects who were virologic failures were 29% with twice-daily fosamprenavir/ritonavir and 27% with lopinavir/ritonavir. The frequency of discontinuations due to adverse events and other reasons, and deaths were similar between treatment arms. Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 81 cells per mm3 with twice-daily fosamprenavir/ritonavir and 91 cells per mm3 with lopinavir/ritonavir. This trial was not large enough to reach definitive conclusion that fosamprenavir/ritonavir and lopinavir/ritonavir are clinically equivalent. Once-daily administration of fosamprenavir plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of subjects receiving fosamprenavir 1,400 mg plus ritonavir 200 mg once daily had plasma HIV-1 RNA less than 400 copies per mL and less than 50 copies per mL, respectively. 14.3 Pediatric Trials Three open-label trials in pediatric subjects aged at least weeks to 18 years were conducted. In one trial (APV29005), twice-daily dosing regimens (fosamprenavir with or without ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged to 18 years. In second trial (APV20002), twice-daily dosing regimens (fosamprenavir with ritonavir) were evaluated in combination with other antiretroviral agents in pediatric subjects aged at least weeks to younger than years. third trial (APV20003) evaluated once-daily dosing of fosamprenavir with ritonavir; the pharmacokinetic data from this trial did not support once-daily dosing regimen in any pediatric patient population. APV29005. Fosamprenavir Twenty (18 therapy-naive and therapy-experienced) pediatric subjects received fosamprenavir calcium oral suspension without ritonavir twice daily. At Week 24, 65% (13 of 20) achieved HIV-1 RNA less than 400 copies per mL, and the median increase from baseline in CD4+ cell count was 350 cells per mm3.. Fosamprenavir Plus Ritonavir. Forty-nine protease inhibitor-naive and 40 protease inhibitor-experienced pediatric subjects received fosamprenavir calcium oral suspension or tablets with ritonavir twice daily. At Week 24, 71% of protease inhibitor-naive (35 of 49) and 55% of protease inhibitor-experienced (22 of 40) subjects achieved HIV-1 RNA less than 400 copies per mL; median increases from baseline in CD4+ cell counts were 184 cells per mm3 and 150 cells per mm3 in protease inhibitor-naive and experienced subjects, respectively.. APV20002. Fifty-four pediatric subjects (49 protease inhibitor-naive and protease inhibitor-experienced) received fosamprenavir calcium oral suspension with ritonavir twice daily. At Week 24, 72% of subjects achieved HIV-1 RNA less than 400 copies per mL. The median increases from baseline in CD4+ cell counts were 400 cells per mm3 in subjects aged at least weeks to younger than months and 278 cells per mm3 in subjects aged months to years.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic properties of amprenavir after administration of fosamprenavir, with or without ritonavir, have been evaluated in both healthy adult volunteers and in HIV-1-infected subjects; no substantial differences in steady-state amprenavir concentrations were observed between the populations. The pharmacokinetic parameters of amprenavir after administration of fosamprenavir (with and without concomitant ritonavir) are shown in Table 7. Table 7. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in AdultsRegimenCmax (mcg/mL)Tmax (hours)Data shown are median (range).AUC24 (mcgoh/mL)Ctau Ctau is the concentration at the end of the dose interval.(mcg/mL)Fosamprenavir1,400 mg Twice Daily(n 22)HIV-infected adults. 4.82(4.06-5.72)1.3(0.8-4.0)33.0AUC24 was calculated from AUC12 summary data 2. (27.6-39.2)0.35(0.27-0.46)Fosamprenavir1,400 mg Once Daily plus Ritonavir 200 mg Once Daily(n 22)Healthy adults. 7.24(6.32-8.28)2.1(0.8-5.0)69.4(59.7-80.8)1.45(1.16-1.81)Fosamprenavir1,400 mg Once Daily plus Ritonavir 100 mg Once Daily(n 36) 7.93(7.25-8.68)1.5(0.75-5.0)66.4(61.1-72.1)0.86(0.74-1.01)Fosamprenavir700 mg Twice Daily plus Ritonavir 100 mg Twice Daily(n 24) 6.08(5.38-6.86)1.5(0.75-5.0)79.2(69.0-90.6)2.12(1.77-2.54)The mean plasma amprenavir concentrations of the dosing regimens over the dosing intervals are displayed in Figure 1. Figure 1. Mean (+-SD) Steady-State Plasma Amprenavir Concentrations and Mean EC50 Values Against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) Absorption. After administration of single dose of fosamprenavir to HIV-1-infected subjects, the time to peak amprenavir concentration (Tmax) occurred between 1.5 and hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of single 1,400-mg dose in the fasted state, fosamprenavir calcium oral suspension (50 mg per mL) and fosamprenavir calcium tablets (700 mg) provided similar amprenavir exposures (AUC); however, the Cmax of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet. Amprenavir is both substrate for and inducer of P-glycoprotein.. Effects of Food on Oral Absorption. Administration of single 1,400 mg-dose of fosamprenavir calcium tablets in the fed state (standardized high-fat meal: 967 kcal, 67 grams fat, 33 grams protein, 58 grams carbohydrate) compared with the fasted state was associated with no significant changes in amprenavir Cmax, Tmax, or AUC0- [see Dosage and Administration (2)]. Distribution. In vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha1-acid glycoprotein. In vitro, concentration-dependent binding was observed over the concentration range of to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations. Metabolism. After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the CYP3A4 enzyme system. The major metabolites result from oxidation of the tetrahydrofuran and aniline moieties. Glucuronide conjugates of oxidized metabolites have been identified as minor metabolites in urine and feces. Elimination. Excretion of unchanged amprenavir in urine and feces is minimal. Unchanged amprenavir in urine accounts for approximately 1% of the dose; unchanged amprenavir was not detectable in feces. Approximately 14% and 75% of an administered single dose of 14C-amprenavir can be accounted for as metabolites in urine and feces, respectively. Two metabolites accounted for greater than 90% of the radiocarbon in fecal samples. The plasma elimination half-life of amprenavir is approximately 7.7 hours. Specific Populations. Patients with Hepatic Impairment. The pharmacokinetics of amprenavir have been studied after the administration of fosamprenavir in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following weeks of dosing with fosamprenavir plus ritonavir, the AUC of amprenavir was increased by approximately 22% in subjects with mild hepatic impairment, by approximately 70% in subjects with moderate hepatic impairment, and by approximately 80% in subjects with severe hepatic impairment compared with HIV-1-infected subjects with normal hepatic function. Protein binding of amprenavir was decreased in subjects with hepatic impairment. The unbound fraction at hours (approximate Cmax) ranged between decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (Cmin) increased from 50% to 102% [see Dosage and Administration (2.4)]. The pharmacokinetics of amprenavir have been studied after administration of amprenavir given as AGENERASE(R) capsules to adult subjects with hepatic impairment. Following administration of single 600-mg oral dose, the AUC of amprenavir was increased by approximately 2.5-fold in subjects with moderate cirrhosis and by approximately 4.5-fold in subjects with severe cirrhosis compared with healthy volunteers [see Dosage and Administration (2.4)]. Patients with Renal Impairment. The impact of renal impairment on amprenavir elimination in adults has not been studied. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir. Pregnant Women Amprenavir pharmacokinetics were studied in pregnant women receiving fosamprenavir (700 mg) plus ritonavir (100 mg) twice daily during the second trimester (n 6) or third trimester (n 9) and postpartum (n 9). Compared to postpartum, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester (Table 8). This decrease results in amprenavir concentrations that are within the range observed across regimens of fosamprenavir in non-pregnant adults and lower concentrations compared with fosamprenavir (700 mg) plus ritonavir (100 mg) twice daily in non-pregnant adults (Table 7, Table 8). This decrease is not expected to be considered clinically relevant in patients who are virologically suppressed; however, viral load should be monitored closely to ensure viral suppression is maintained [see Dosage and Administration (2.2), Use in Specific Populations (8.1)]. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n 7) was 0.27 (0.24 to 0.30).Table 8. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in Pregnant Women Receiving Fosamprenavir with RitonavirPharmacokineticParameterFosamprenavir 700 mg Twice Daily plus Ritonavir 100 mg Twice DailySecond Trimester(n 6)Third Trimester(n 9)Postpartum(n 9)AUC12 (mcgoh/mL)26.0(19.5, 34.6)30.1(21.6, 41.9)39.9(31.9, 50.1)AUC24 (mcgoh/mL)AUC24 was calculated from AUC12 summary data 2. 52.0(39.0, 69.2)60.2(43.2, 83.8)79.8(63.8, 100.2)Cmax (mcg/mL)4.19(3.19, 5.51)5.36(3.98, 7.22)6.65(5.24, 8.44)Ctau (mcg/mL)Ctau represents the concentration at the end of the dose interval. 1.31(0.97, 1.77)1.34(0.95, 1.89)2.03(1.46, 2.83). Pediatric Patients. The pharmacokinetics of amprenavir following administration of fosamprenavir calcium oral suspension and fosamprenavir calcium tablets, with or without ritonavir, have been studied in total of 212 HIV-1-infected pediatric subjects enrolled in trials. Fosamprenavir without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged to years. Fosamprenavir with ritonavir was administered as fosamprenavir 30 mg per kg plus ritonavir mg per kg once daily to children aged to 18 years and as fosamprenavir 18 to 60 mg per kg plus ritonavir to 10 mg per kg twice daily to children aged at least weeks to 18 years; body weights ranged from to 103 kg.Amprenavir apparent clearance decreased with increasing weight. Weight-adjusted apparent clearance was higher in children younger than years, suggesting that younger children require higher mg-per-kg dosing of fosamprenavir.The pharmacokinetics of fosamprenavir calcium oral suspension in protease inhibitor-naive infants younger than months (n 9) receiving fosamprenavir 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC12 and Cmin than adults receiving twice-daily fosamprenavir 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC12, Cmax, and Cmin were 26.6 mcgohour per mL, 6.25 mcg per mL, and 0.86 mcg per mL, respectively. Because of expected low amprenavir exposure and requirement for large volume of drug, twice-daily dosing of fosamprenavir alone (without ritonavir) in pediatric subjects younger than years was not studied.Pharmacokinetic parameters for fosamprenavir administered with food and with ritonavir in this patient population at the recommended weight-band-based dosage regimens are provided in Table 9. Table 9. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters by Weight in Pediatric and Adolescent Subjects Aged at Least Weeks to 18 Years Receiving Fosamprenavir with RitonavirWeightRecommended Dosage RegimenCmax AUC24 Cmin n(mcg/mL)n(mcgoh/mL)n(mcg/mL)< 11 kgFosamprenavir 45 mg/kg plus Ritonavir mg/kg twice daily126.00(3.88, 9.29)1257.3(34.1, 96.2)271.65(1.22, 2.24)11 kg < 15 kgFosamprenavir 30 mg/kg plus Ritonavir mg/kg twice dailyNot studiedRecommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis. 15 kg < 20 kgFosamprenavir 23 mg/kg plus Ritonavir mg/kg twice daily59.54(4.63, 19.7)5121(54.2, 269)93.56(2.33, 5.43)20 kg < 39 kgFosamprenavir 18 mg/kg plus Ritonavir mg/kg twice daily136.24(5.01, 7.77)1297.9(77.0, 124)232.54(2.11, 3.06)>= 39 kgFosamprenavir 700 mg plus Ritonavir 100 mg twice daily155.03(4.04, 6.26)1572.3(59.6, 87.6)421.98(1.72, 2.29)Subjects aged to younger than years receiving fosamprenavir 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir Cmax (n 9), AUC12 (n 9), and Cmin (n 19) of 7.15 (5.05, 10.1), 22.3 (15.3, 32.6), and 0.513 (0.384, 0.686), respectively.. Geriatric Patients. The pharmacokinetics of amprenavir after administration of fosamprenavir to patients older than 65 years have not been studied [see Use in Specific Populations (8.5)]. Male and Female Patients. The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between males and females. Racial Groups. The pharmacokinetics of amprenavir after administration of fosamprenavir do not differ between blacks and non-blacks. Drug Interaction Studies. [See Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7).]Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system. Amprenavir inhibits CYP3A4. Data also suggest that amprenavir induces CYP3A4. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Amprenavir does not inhibit CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1, or uridine glucuronosyltransferase (UDPGT). Amprenavir is both substrate for and inducer of P-glycoprotein. Drug interaction trials were performed with fosamprenavir and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, Cmax, and Cmin values are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of fosamprenavir on other drugs). In addition, since fosamprenavir delivers comparable amprenavir plasma concentrations as AGENERASE, drug interaction data derived from trials with AGENERASE are provided in Tables 11 and 13. For information regarding clinical recommendations, [see Drug Interactions (7)]. Table 10. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of Fosamprenavir in the Presence of the Coadministered Drug(s) Increase; Decrease; <-> No change or less than or equal to 10%), NA Not applicable.Coadministered Drug(s) and Dose(s)Dose of FosamprenavirConcomitant medication is also shown in this column where appropriate.n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)Cmax AUCCmin Antacid (MAALOX TC) 30-mL single dose1,400-mg single dose3035(24 to 42)18(9 to 26)14(7 to 39)Atazanavir 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days22<-><-><->Atorvastatin 10 mg once daily for days 1,400 mg twice daily for weeks1618(34 to 1)27(41 to 12)12(27 to 6)Atorvastatin 10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-><->Efavirenz 600 mg once daily for weeks 1,400 mg once daily plus ritonavir 200 mg once daily for weeks16<->13(30 to 7)36(8 to 56)Efavirenz 600 mg once daily plus additional ritonavir 100 mg once daily for weeks 1,400 mg once daily plus ritonavir 200 mg once daily for weeks1618(1 to 38)11(0 to 24)<->Efavirenz 600 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><->17(4 to 29)Esomeprazole 20 mg once daily for weeks 1,400 mg twice daily for weeks25<-><-><->Esomeprazole 20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><-><->Ethinyl estradiol/norethindrone 0.035 mg/0.5 mg once daily for 21 days 700 mg twice daily plus ritonavirRitonavir Cmax, AUC, and Cmin increased by 63%, 45%, and 13%, respectively, compared with historical control. 100 mg twice daily for 21 days25<->Compared with historical control. <-> <-> KetoconazoleSubjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for days15<-><-><->Lopinavir/ritonavir 533 mg/133 mg twice daily 1,400 mg twice daily for weeks1813Compared with fosamprenavir 700 mg/ritonavir 100 mg twice daily for weeks. 26 42 Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks1858(42 to 70)63(51 to 72)65(54 to 73)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 20 days1434(25 to 41)35(29 to 41)36(27 to 43)Maraviroc300 mg once daily for 10 days1,400 mg once daily plus ritonavir 100 mg once daily for 20 days1429(20 to 38)30(23 to 36)15(3 to 25)Methadone 70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19<-> <-> <-> Nevirapine 200 mg twice daily for weeksSubjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for weeks1725(37 to 10)33(45 to 20)35(50 to 15)Nevirapine 200 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks17<->11(23 to 3)19(32 to 4)Phenytoin 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days13<->20(8 to 34)19(6 to 33)Raltegravir 400 mg twice daily for 14 days 1,400 mg twice daily for 14 days (fasted)1427(46 to <->)36(53 to 13)43Clast (C12 or C24 h). (59 to 21)1,400 mg twice daily for 14 daysDoses of fosamprenavir and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days. 1415(27 to 1)17(27 to 6)32 (53 to 1)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days (fasted)1414(39 to 20)17(38 to 12)20 (45 to 17)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days 1225(42 to 2)25(44 to <->)33 (52 to 7)Raltegravir 400 mg twice daily for 14 days 1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted)1318(34 to <->)24(41 to <->)50 (64 to 31)1,400 mg once daily plus ritonavir 100 mg once daily for 14 days 1427(1 to 62)13(7 to 38)17 (45 to 26)Ranitidine 300-mg single dose (administered hour before fosamprenavir) 1,400-mg single dose3051(43 to 58)30(22 to 37)<->(19 to 21)Rifabutin 150 mg every other day for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1536 (18 to 55)35 (17 to 56)17 (1 to 39)Tenofovir 300 mg once daily for to 48 weeks 700 mg twice daily plus ritonavir 100 mg twice daily for to 48 weeks45NANA<->Compared with parallel control group. Tenofovir 300 mg once daily for to 48 weeks 1,400 mg once daily plus ritonavir 200 mg once daily for to 48 weeks60NANA<-> Table 11. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of AGENERASE in the Presence of the Coadministered Drug(s) Increase; Decrease; <-> No change or less than 10%); NA Cmin not calculated for single-dose trial.Coadministered Drug(s) and Dose(s)Dose of AGENERASECompared with parallel control group.n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)Cmax AUCCmin Abacavir300 mg twice daily for to weeks 900 mg twice daily for to weeks4<-> <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice daily for days1215(1 to 31)18(8 to 29)39(31 to 47)Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days940Median percent change; confidence interval not reported. 130 125 Ethinyl estradiol/norethindrone 0.035 mg/1 mg for cycle 1,200 mg twice daily for 28 days10<->22(35 to 8)20(41 to 8)Indinavir 800 mg times day for weeks (fasted) 750 or 800 mg times day for weeks (fasted)918(13 to 58)33(2 to 73)25(27 to 116)Ketoconazole400-mg single dose 1,200-mg single dose1216(25 to 6)31(20 to 42)NALamivudine150-mg single dose 600-mg single dose11<-><->NAMethadone44 to 100 mg once daily for> 30 days 1,200 mg twice daily for 10 days1627Compared with historical data. 30 25 Nelfinavir750 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)614(38 to 20)<->189(52 to 448)Rifabutin300 mg once daily for 10 days 1,200 mg twice daily for 10 days5<->15(28 to 0)15(38 to 17)Rifampin300 mg once daily for days 1,200 mg twice daily for days1170(76 to 62)82(84 to 78)92(95 to 89)Saquinavir800 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)737(54 to 14)32(49 to 9)14(52 to 54)Zidovudine300-mg single dose 600-mg single dose12<->13(2 to 31)NATable 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Fosamprenavir Increase; Decrease; <-> No change or less than 10%); ND Interaction cannot be determined as Cmin was below the lower limit of quantitation.Coadministered Drug(s) and Dose(s)Dose of FosamprenavirConcomitant medication is also shown in this column where appropriate.n% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)Cmax AUCCmin Atazanavir 300 mg once daily for 10 daysComparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily for 10 days. 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days2124(39 to 6)22(34 to 9)<->Atorvastatin 10 mg once daily for days 1,400 mg twice daily for weeks16304(205 to 437)130(100 to 164)10(27 to 12)Atorvastatin 10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16184(126 to 257)153(115 to 199)73(45 to 108)Esomeprazole 20 mg once daily for weeks 1,400 mg twice daily for weeks25<->55(39 to 73)NDEsomeprazole 20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><->NDEthinyl estradiolAdministered as combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg. 0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days2528(21 to 35)37(30 to 42)NDDolutegravir50 mg once daily700 mg twice daily plus ritonavir 100 mg twice daily1224(8 to 37)35(22 to 46)49(37 to 59)KetoconazoleSubjects were receiving fosamprenavir/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir/ritonavir. 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for days1525(0 to 56)169(108 to 248)NDLopinavir/ritonavirData represent lopinavir concentrations. 533 mg/133 mg twice daily for weeks 1,400 mg twice daily for weeks18<->Compared with lopinavir 400 mg/ritonavir 100 mg twice daily for weeks. <-> <-> Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1830(15 to 47)37(20 to 55)52(28 to 82)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 20 days1452(27 to 82)149(119 to 182)374(303 to 457)Maraviroc300 mg once daily for 10 days1,400 mg once daily plus ritonavir 100 mg once daily for 20 days1445(20 to 74)126(99 to 158)80(53 to 113)Methadone 70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19R-Methadone (active)21Dose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged. (30 to 12)18 (27 to 8)11 (21 to 1)S-Methadone (inactive)43 (49 to 37)43 (50 to 36)41 (49 to 31)Nevirapine 200 mg twice daily for weeksSubjects were receiving nevirapine for at least 12 weeks prior to trial. 1,400 mg twice daily for weeks1725(14 to 37)29(19 to 40)34(20 to 49)Nevirapine 200 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1713(3 to 24)14(5 to 24)22(9 to 35)Norethindrone 0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days2538(32 to 44)34(30 to 37)26(20 to 32)Phenytoin 300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily for 10 days1420(12 to 27)22(17 to 27)29(23 to 34)Rifabutin 150 mg every other day for weeksComparison arm of rifabutin 300 mg once daily for weeks. AUC is AUC(0-48 h). 700 mg twice daily plus ritonavir 100 mg twice daily for weeks1514(28 to 4)<->28(12 to 46)(25-O-desacetylrifabutin metabolite)579(479 to 698)1,120(965 to 1,300)2,510(1,910 to 3,300)Rifabutin 25-O-desacetylrifabutin metaboliteNA64(46 to 84)NARosuvastatin10-mg single dose700 mg twice daily plus ritonavir 100 mg twice daily for days458NATable 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of AGENERASE Increase; Decrease; <-> No change or less than 10%); NA Cmin not calculated for single-dose trial; ND Interaction cannot be determined as Cmin was below the lower limit of quantitation.Coadministered Drug(s) and Dose(s)Dose of AGENERASEn% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)Cmax AUCCmin Abacavir300 mg twice daily for to weeks 900 mg twice daily for to weeks4<->Compared with historical data. <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice daily for days1210(24 to 7)<-><->Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days947Median percent change; confidence interval not reported. 61 88 Ethinyl estradiol0.035 mg for cycle 1,200 mg twice daily for 28 days10<-><->32(3 to 79)Indinavir800 mg times day for weeks (fasted) 750 mg or 800 mg times day for weeks (fasted)922 38 27 Ketoconazole400-mg single dose 1,200-mg single dose1219(8 to 33)44(31 to 59)NALamivudine150-mg single dose 600-mg single dose11<-><->NAMethadone44 mg to 100 mg once daily for 30 days 1,200 mg twice daily for 10 days16R-Methadone (active)25(32 to 18)13(21 to 5)21(32 to 9)S-Methadone (inactive)48(55 to 40)40(46 to 32)53(60 to 43)Nelfinavir750 mg times day for weeks (fed) 750 mg or 800 mg times day for weeks (fed)612 15 14 Norethindrone1 mg for cycle 1,200 mg twice daily for 28 days10<->18(1 to 38)45(13 to 88)Rifabutin300 mg once daily for 10 days 1,200 mg twice daily for 10 days5119(82 to 164)193(156 to 235)271(171 to 409)Rifampin300 mg once daily for days 1,200 mg twice daily for days11<-><->NDSaquinavir800 mg times day for weeks (fed) 750 mg or 800 mg times day for weeks (fed)721 19 48 Zidovudine300-mg single dose 600-mg single dose1240(14 to 71)31(19 to 45)NA. Figure 1. Mean (+-SD) Steady-State Plasma Amprenavir Concentrations and Mean EC50 Values Against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum).

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk Summary. Limited data are available for use of fosamprenavir in pregnancy. Fosamprenavir 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data). There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir. In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD.In the rat pre- and postnatal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately times the exposure in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir (see Data). Clinical Considerations. Virologic Monitoring During Pregnancy and the Postpartum Period Based on limited data on the use of fosamprenavir during pregnancy, no dosage adjustments are required for pregnant patients who are already on stable twice-daily regimen of fosamprenavir 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. In clinical trial of 10 HIV-1-infected pregnant women treated with fosamprenvir 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period. Therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Data, Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Pregnancy data with other dosage regimens of fosamprenavir (with or without ritonavir) are not available.. Data. Human Data Fosamprenavir 700 mg taken with ritonavir 100 mg twice daily in combination with background regimen was evaluated in clinical trial of 10 HIV-1-infected pregnant women during the second and third trimesters and postpartum. Subjects initiated fosamprenavir/ritonavir during pregnancy at median of 19 weeks gestation; had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation. Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n 6) or third trimester (n 9) and postpartum (n 9). Pregnancy outcomes were available for all 10 subjects, among which twin pregnancy was included. Compared to the postpartum period, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n 7) was 0.27 (0.24 to 0.30) [see Clinical Pharmacology (12.3)]. At delivery, subjects had HIV-1 viral load less than 50 copies/mL, and subject had viral load of 111 copies/mL. All 11 infants born had test results that were negative for HIV-1 at the time of delivery and through 12 months postpartum. There were no new safety findings compared with the known safety profile of fosamprenavir/ritonavir in HIV-1-infected adults.Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens, there were birth defects reported in 109 first trimester exposures and birth defects reported in 36 second and third trimester exposures. The background rate for major birth defects is 2.7% in U.S. reference population of the MACDP. Prospective reports from the APR of overall major birth defects in pregnancies exposed to fosamprenavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease.. Animal Data Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on Gestation Days to 17 and Days to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC0-24 h) approximately times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir. However, increased incidence of abortion was observed in rabbits administered maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on Gestation Days to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD.In the rat pre- and postnatal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on Gestation Day to Lactation/Postpartum Day 20. Fosamprenavir caused reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed. Systemic exposure (AUC0-24 h) to amprenavir in rats was approximately times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.