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 calcium, 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 calcium (with and without concomitant ritonavir) are shown in Table 7.Table 7. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in AdultsRegimenC max (mcg/mL)T max (hours) AUC 24 (mcgoh/mL)C tau (mcg/mL)Fosamprenavir calcium 1,400 mg Twice Daily(n 22) 4.82(4.06 to 5.72)1.3(0.8to 4)33 (27.6to 39.2)0.35(0.27to 0.46)Fosamprenavir calcium 1,400 mg Once Daily plus Ritonavir 200 mg Once Daily (n 22) 7.24(6.32 to 8.28)2.1(0.8t 5)69.4(59.7 to 80.8)1.45(1.16 to 1.81)Fosamprenavir calcium 1,400 mg Once Daily plus Ritonavir 100 mg Once Daily (n 36) 7.93(7.25 to 8.68)1.5(0.75 to 5)66.4(61.1 to 72.1)0.86(0.74 to 1.01)Fosamprenavir calcium 700 mg Twice Daily plus Ritonavir 100 mg Twice Daily (n 24) 6.08(5.38 to 6.86)1.5(0.75 to 5)79.2 (69 to 90.6)2.12(1.77 to 2.54)aData shown are median (range). bC tauis the concentration at the end of the dose interval. cHIV-infected adults. dAUC 24was calculated from AUC 12summary data 2. eHealthy adults. 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 EC 50Values against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) AbsorptionAfter administration of single dose of fosamprenavir calcium to HIV-1-infected subjects, the time to peak amprenavir concentration (T max) occurred between 1.5 and hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium 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 maxof 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 AbsorptionAdministration 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 max, max, or AUC 0- [see Dosage and Administration (2)]. Administration of single 1,400 mg dose of fosamprenavir calcium oral suspension 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 46% reduction in max, 0.72-hour delay in max, and 28% reduction in amprenavir AUC 0-. DistributionIn vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha 1-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. MetabolismAfter 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.EliminationExcretion 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 PopulationsPatients with Hepatic Impairment: The pharmacokinetics of amprenavir have been studied after the administration of fosamprenavir calcium in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following weeks of dosing with fosamprenavir calcium 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 max) ranged between decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (C min) 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 calcium (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 calcium in non-pregnant adults and lower concentrations compared with fosamprenavir calcium (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 calcium with RitonavirPharmacokinetic ParameterFosamprenavir calcium 700 mg Twice Daily plus Ritonavir 100 mg Twice DailySecond Trimester(n 6)Third Trimester(n 9)Postpartum(n 9)AUC 12(mcgoh/mL) 26.0(19.5, 34.6)30.1(21.6, 41.9)39.9(31.9, 50.1)AUC 24(mcgoh/mL) 52.0(39.0, 69.2)60.2(43.2, 83.8)79.8(63.8, 100.2)C max(mcg/mL) 4.19(3.19, 5.51)5.36(3.98, 7.22)6.65(5.24, 8.44)C tau(mcg/mL) 1.31(0.97, 1.77)1.34(0.95, 1.89)2.03(1.46, 2.83)aAUC 24was calculated from AUC 12summary data 2. bC taurepresents the concentration at the end of the dose interval. 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 calcium without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged to years. Fosamprenavir calcium with ritonavir was administered as fosamprenavir calcium 30 mg per kg plus ritonavir mg per kg once daily to children aged to 18 years and as fosamprenavir calcium 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 calcium.The pharmacokinetics of fosamprenavir calcium oral suspension in protease inhibitor-naive infants younger than months (n 9) receiving fosamprenavir calcium 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC 12and minthan adults receiving twice-daily fosamprenavir calcium 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC 12, max, and minwere 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 calcium alone (without ritonavir) in pediatric subjects younger than years was not studied. Pharmacokinetic parameters for fosamprenavir calcium 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 Calcium with RitonavirWeightRecommended Dosage RegimenC max AUC 24 min n(mcg/mL)n(mcgoh/mL)n(mcg/mL)< 11 kgFosamprenavir calcium 45 mg/kg plus Ritonavir mg/kg twice daily126 (3.88, 9.29)1257.3(34.1, 96.2)271.65(1.22, 2.24)11 kg < 15 kgFosamprenavir calcium 30 mg/kg plus Ritonavir mg/kg twice dailyNot studied 15 kg < 20 kgFosamprenavir calcium 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 calcium 18 mg/kg plus Ritonavir mg/kg twice daily136.24(5.01, 7.77)1297.9(77, 124)232.54(2.11, 3.06)>= 39 kgFosamprenavir calcium 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)aRecommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis. Subjects aged to younger than years receiving fosamprenavir calcium 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir max(n 9), AUC 12(n 9), and min(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 calcium 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 calcium do not differ between males and females. Racial Groups:The pharmacokinetics of amprenavir after administration of fosamprenavir calcium 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 calcium and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, max, and minvalues are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of fosamprenavir calcium on other drugs). In addition, since fosamprenavir calcium 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 Calcium in the Presence of the Coadministered Drug(s)Coadministered Drug(s) and Dose(s)Dose of Fosamprenavir Calcium n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)C max AUCC min Antacid (MAALOX TC)30 mL single dose1,400-mgsingle dose30 35( 24 to 42) 18( to 26) 14( to 39)Atazanavir300 mg once daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 10 days22<-><-><->Atorvastatin10 mg once daily for days1,400 mg twice daily for weeks16 18( 34 to 1) 27( 41 to 12) 12( 27 to 6)Atorvastatin10 mg once daily for days700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-><->Efavirenz600 mg once daily for weeks1,400 mg once daily plus ritonavir 200 mg once daily for weeks16<-> 13( 30 to 7) 36( to 56)Efavirenz600 mg once daily plus additional ritonavir 100 mg once daily for weeks1,400 mg once daily plus ritonavir 200 mg once daily for weeks16 18( to 38) 11(0 to 24)<->Efavirenz600 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-> 17( to 29)Esomeprazole20 mg once daily for weeks1,400 mg twice daily for weeks25<-><-><->Esomeprazole20 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><-><->Ethinyl estradiol/norethindrone0.035 mg/0.5 mg once daily for 21 days700 mg twice daily plus ritonavir b100 mg twice daily for 21 days 25<-> <-> <-> Ketoconazole 200 mg once daily for days700 mg twice daily plus ritonavir 100 mg twice daily for days15<-><-><->Lopinavir/ritonavir533 mg/133 mg twice daily1,400 mg twice daily for weeks18 13 26 42 Lopinavir/ritonavir400 mg/100 mg twice daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks18 58( 42 to 70) 63( 51 to 72) 65( 54 to 73)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir100 mg twice daily for20 days14 34( 25 to 41) 35( 29 to 41) 36( 27 to 43)Maraviroc300 mg once daily for 10 days1,400 mg once dailyplus ritonavir100 mg once daily for20 days14 29( 20 to 38)30(23 to 36) 15(3 to 25)Methadone70 to 120 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks19<-> <-> <-> Nevirapine200 mg twice daily for weeks 1,400 mg twice daily for weeks17 25( 37 to 10) 33( 45 to 20) 35( 50 to 15)Nevirapine200 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)Phenytoin300 mg once daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 10 days13<-> 20( to 34) 19( to 33)Raltegravir400 mg twice daily for 14 days1,400 mg twice daily for 14 days (fasted)14 27( 46 to <->) 36( 53 to 13) 43 ( 59 to 21)1,400 mg twice daily for 14 days 14 15( 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)14 14( 39 to 20) 17( 38 to 12) 20 ( 45 to 17)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days12 25( 42 to 2) 25( 44 to <->) 33 ( 52 to 7)Raltegravir400 mg twice daily. for 14 days1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted)13 18( 34 to <->) 24( 41 to <->) 50 ( 64 to 31)1,400 mg once daily plus ritonavir 100 mg once daily for 14 days 14 27( to 62) 13( to 38) 17 ( 45 to 26)Ranitidine300 mg single dose (administered hour before fosamprenavir)1,400 mg single dose30 51( 43 to 58) 30( 22 to 37)<->( 19 to 21)Rifabutin150 mg every other day for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks15 36 ( 18 to 55) 35 ( 17 to 56) 17 ( to 39)Tenofovir300 mg once daily for to 48 weeks700 mg twice daily plus ritonavir 100 mg twice daily for to 48 weeks45NANA<-> Tenofovir300 mg once daily for to 48 weeks1,400 mg once daily plus ritonavir 200 mg once daily for to 48 weeks60NANA<-> aConcomitant medication is also shown in this column where appropriate. bRitonavir max, AUC, and minincreased by 63%, 45%, and 13%, respectively, compared with historical control. cCompared with historical control. dSubjects were receiving fosamprenavir calcium/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir calcium/ritonavir. eCompared with fosamprenavir calcium 700 mg/ritonavir 100 mg twice daily for weeks. fSubjects were receiving nevirapine for at least 12 weeks prior to trial. gC last(C 12 hor 24 h). hDoses of fosamprenavir calcium and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days. iN 18 for min. jCompared with parallel control group. Increase; Decrease; <-> No change or less than or equal to 10%), NA Not applicable.Table 11. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of Agenerase in the Presence of the Coadministered Drug(s)Coadministered Drug(s) and Dose(s)Dose ofAgenerase n% Change in Amprenavir Pharmacokinetic Parameters(90% CI)C max AUCC min Abacavir300 mg twice daily for to weeks 900 mg twice dailyfor to weeks4<-> <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice dailyfor days12 15( to 31) 18( to 29) 39( 31 to 47)Delavirdine600 mg twice daily for 10 days 600 mg twice dailyfor 10 days9 40 130 125 Ethinyl estradiol/norethindrone0.035 mg/1 mg for cycle 1,200 mg twice dailyfor 28 days10<-> 22( 35 to 8) 20( 41 to 8)Indinavir800 mg times day for weeks (fasted) 750 or 800 mg times day for weeks (fasted)9 18( 13 to 58) 33( to 73) 25( 27 to 116)Ketoconazole400-mg single dose 1,200-mgsingle dose12 16( 25 to 6) 31( 20 to 42)NALamivudine150-mg single dose 600-mgsingle dose11<-><->NAMethadone44 to 100 mg once daily for 30 days1,200 mg mg twice dailyfor 10 days16 27 30 25 Nelfinavir750 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)6 14( 38 to 20)<-> 189( 52 to 448)Rifabutin300 mg once daily for 10 days 1,200 mg twice dailyfor 10 days5<-> 15( 28 to 0) 15( 38 to 17)Rifampin300 mg once daily for days 1,200 mg twice dailyfor days11 70( 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)7 37( 54 to 14) 32( 49 to 9) 14( 52 to 54)Zidovudine300-mg single dose 600-mgsingle dose12<-> 13( to 31)NAaCompared with parallel control group. bMedian percent change; confidence interval not reported. cCompared with historical data. Increase; Decrease; <-> No change or less than 10%); NA C minnot calculated for single-dose trial. Table 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Fosamprenavir CalciumCoadministered Drug(s)and Dose(s)Dose ofFosamprenavir Calcium n% Change in Pharmacokinetic Parameters of Coadministered Drug(90% CI)C max AUCC min Atazanavir300 mg once daily for 10 days b700 mg twice daily plus ritonavir 100 mg twice daily for 10 days21 24( 39 to 6) 22( 34 to 9)<->Atorvastatin10 mg once daily for days 1,400 mg twice daily for weeks16 304( 205 to 437) 130( 100 to 164) 10( 27 to 12)Atorvastatin10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16 184( 126 to 257) 153( 115 to 199) 73( 45 to 108)Esomeprazole20 mg once daily for weeks 1,400 mg twice daily for weeks25<-> 55( 39 to 73)NDEsomeprazole20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><->NDEthinyl estradiol 0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days25 28( 21 to 35) 37( 30 to 42)NDDolutegravir 50 mg once daily700 mg twice daily plus ritonavir 100 mg twice daily1224 (8 to 37)35 (22 to 46)49 (37 to 59)Ketoconazole 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice dailyfor days15 25( to 56) 169( 108 to 248)NDLopinavir/ritonavir 533 mg/133 mg twice daily for weeks 1,400 mg twice daily for weeks18<-> <-> <-> Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks18 30( 15 to 47) 37( 20 to 55) 52( 28 to 82)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir100 mg twice daily for20 days14 52( 27 to 82) 149( 119 to 182) 374( 303 to 457)Maraviroc300 mg once daily for 10 days1,400 mg once dailyplus ritonavir100 mg once daily for20 days14 45( 20 to 74) 126( 99 to 158) 80( 53 to 113)Methadone70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19R-Methadone (active) 21 ( 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)Nevirapine200 mg twice daily for weeks 1,400 mg twice daily for weeks17 25( 14 to 37) 29( 19 to 40) 34( 20 to 49)Nevirapine200 mg twice daily for weeks h700 mg twice daily plus ritonavir 100 mg twice daily for weeks17 13( to 24) 14( to 24) 22( to 35)Norethindrone 0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days25 38( 32 to 44) 34( 30 to 37) 26( 20 to 32)Phenytoin300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily. for 10 days14 20( 12 to 27) 22( 17 to 27) 29( 23 to 34)Rifabutin150 mg every other day for weeks i700 mg twice daily plus ritonavir 100 mg twice daily for weeks15 14( 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 metaboliteNA 64( 46 to 84)NARosuvastatin10 mg single dose700 mg twice dailyplus ritonavir100 mg twice dailyfor7 days( 45)( 8) NAaConcomitant medication is also shown in this column where appropriate. bComparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily for 10 days. cAdministered as combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg. dSubjects were receiving fosamprenavir calcium/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir calcium/ritonavir. eData represent lopinavir concentrations. fCompared with lopinavir 400 mg/ritonavir 100 mg twice daily for weeks. gDose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged. hSubjects were receiving nevirapine for at least 12 weeks prior to trial. iComparison arm of rifabutin 300 mg once daily for weeks. AUC is AUC(0-48 h). Increase; Decrease; <-> No change or less than 10%); ND Interaction cannot be determined as minwas below the lower limit of quantitation. Table 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Agenerase Coadministered Drug(s) and Dose(s)Dose ofAgenerasen% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)C max AUCC min 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 days12 10( 24 to 7)<-><->Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days9 47 61 88 Ethinyl estradiol0.035 mg for cycle 1,200 mg twice daily for 28 days10<-><-> 32( to 79)Indinavir800 mg times day for weeks (fasted) 750 mg or 800 mg times day for weeks (fasted)9 22 38 27 Ketoconazole400 mg single dose 1,200 mg single dose12 19( to 33) 44( 31 to 59)NALamivudine150 mg single dose 600 mg single dose11<-><->NAMethadone44 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)6 12 15 14 Norethindrone1 mg for cycle 1,200 mg twice daily for 28 days10<-> 18( 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)7 21 19 48 Zidovudine300 mg single dose 600 mg single dose12 40( 14 to 71) 31( 19 to 45)NAaCompared with historical data. bMedian percent change; confidence interval not reported. Increase; Decrease; <->= No change (or less than 10%); NA C minnot calculated for single-dose trial; ND Interaction cannot be determined as minwas below the lower limit of quantitation. image1. 12.4 Microbiology. Mechanism of ActionFosamprenavir 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 ActivityFosamprenavir 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 (EC 50) 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 EC 50value of amprenavir against HIV-1 isolates from clades to was 0.00095 microM in peripheral blood mononuclear cells (PBMCs). Similarly, the EC 50values for amprenavir against monocytes/macrophage tropic HIV-1 isolates (clade B) ranged from 0.003 to 0.075 microM in monocyte/macrophage cultures. The EC 50values 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. ResistanceHIV-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 calcium. Of the 488 antiretroviral-naive subjects treated with fosamprenavir calcium 1,400 mg twice daily or fosamprenavir calcium 1,400 mg plus ritonavir 200 mg once daily in Trials APV30001 and APV30002, respectively, isolates from 61 subjects (29 receiving fosamprenavir calcium and 32 receiving fosamprenavir calcium/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 calcium 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 calcium/ritonavir for 48 weeks in Trial APV30002. However, the M46I and I50V substitutions were detected in isolates from virologic failure subject receiving fosamprenavir calcium/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-ResistanceVarying 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 calcium /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 calcium/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 Substitutions Protease Inhibitor Resistance- Associated Substitutions Fosamprenavir Calcium/Ritonavir Twice DailyLopinavir/Ritonavir Twice Daily(n 88)(n 85)D30N21/2295%17/1989%N88D/S20/2291%12/12100%L90M16/3152%17/2959%M46I/L11/2250%12/2450%V82A/F/T/S2/922%6/1735%I54V2/1118%6/1155%I84V1/617%2/540%aResults should be interpreted with caution because the subgroups were small. bMost subjects had greater than protease inhibitor resistance-associated substitution at baseline. The virologic response based upon baseline phenotype was assessed. Baseline isolates from protease inhibitor-experienced subjects responding to fosamprenavir calcium/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 calcium.Isolates from 15 of the 20 subjects receiving twice-daily fosamprenavir calcium/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 calcium/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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Severe or life-threatening skin reactions have been reported with the use of fosamprenavir calcium [see Warnings and Precautions (5.2)]. The most common moderate to severe adverse reactions in clinical trials of fosamprenavir calcium were diarrhea, rash, nausea, vomiting, and headache.Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir calcium and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir calcium (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.. Severe or life-threatening skin reactions have been reported with the use of fosamprenavir calcium [see Warnings and Precautions (5.2)]. The most common moderate to severe adverse reactions in clinical trials of fosamprenavir calcium were diarrhea, rash, nausea, vomiting, and headache.. Treatment discontinuation due to adverse events occurred in 6.4% of subjects receiving fosamprenavir calcium and in 5.9% of subjects receiving comparator treatments. The most common adverse reactions leading to discontinuation of fosamprenavir calcium (incidence less than or equal to 1% of subjects) included diarrhea, nausea, vomiting, AST increased, ALT increased, and rash.. In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. (6.1)Vomiting and neutropenia were more frequent in pediatrics than in adults. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. In adults the most common adverse reactions (incidence greater than or equal to 4%) are diarrhea, rash, nausea, vomiting, and headache. (6.1). Vomiting 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 TrialsThe 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 calcium 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 calcium 1,400 mg once daily plus ritonavir 200 mg once daily; 24% received fosamprenavir calcium 1,400 mg twice daily; and 15% received fosamprenavir calcium 700 mg twice daily plus ritonavir 100 mg twice daily.Selected adverse reactions reported during the clinical efficacy trials of fosamprenavir calcium 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 ReactionAPV30001 APV30002 Fosamprenavir Calcium 1,400 mg Twice Daily(n 166)Nelfinavir1,250 mgTwice Daily (n 83)Fosamprenavir Calcium 1,400 mgandRitonavir 200 mg Once Daily(n 322)Nelfinavir1,250 mg Twice Daily(n 327)GastrointestinalDiarrhea5%18%10%18%Nausea7%4%7%5%Vomiting2%4%6%4%Abdominal pain1%0%2%2%SkinRash8%2%3%2%General disordersFatigue2%1%4%2%Nervous systemHeadache2%4%3%3%aAll subjects also received abacavir and lamivudine twice daily. 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 ReactionFosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily (n 106)Lopinavir 400 mg andRitonavir 100 mg Twice Daily (n 103)GastrointestinalDiarrhea13%11%Nausea3%9%Vomiting3%5%Abdominal pain< 1%2%SkinRash3%0%Nervous systemHeadache4%2%aAll subjects also received reverse transcriptase inhibitors. Skin rash (without regard to causality) occurred in approximately 19% of subjects treated with fosamprenavir calcium 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 calcium and had median duration of 13 days. Skin rash led to discontinuation of fosamprenavir calcium in less than 1% of subjects. In some subjects with mild or moderate rash, dosing with fosamprenavir calcium was often continued without interruption; if interrupted, reintroduction of fosamprenavir calcium generally did not result in rash recurrence.The percentages of subjects with Grade or laboratory abnormalities in the clinical efficacy trials of fosamprenavir calcium 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 APV30002Laboratory AbnormalityAPV30001 APV30002 Fosamprenavir Calcium 1,400 mg Twice Daily(n 166)Nelfinavir1,250 mg Twice Daily(n 83)Fosamprenavir Calcium 1,400 mg and Ritonavir 200 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%Triglycerides b(> 750 mg/dL) 0%1%6%2%Neutrophil count, absolute (< 750 cells/mm 3) 3%6%3%4%aAll subjects also received abacavir and lamivudine twice daily. bFasting specimens. ULN Upper limit of normal.The incidence of Grade or hyperglycemia in antiretroviral-naive subjects who received fosamprenavir calcium 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 APV30003Laboratory AbnormalityFosamprenavir Calcium 700 mg and Ritonavir 100 mg Twice Daily (n 104)Lopinavir 400 mg andRitonavir 100 mg Twice Daily (n 103)Triglycerides b(> 750 mg/dL) 11% 6% Serum lipase (> x ULN)5%12%ALT (> x ULN)4%4%AST (> x ULN)4%2%Glucose (> 251 mg/dL)2% 2% aAll subjects also received reverse transcriptase inhibitors. bFasting specimens. cn 100 for fosamprenavir calcium plus ritonavir, = 98 for lopinavir plus ritonavir. ULN Upper limit of normal.Pediatric TrialsFosamprenavir calcium 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 calcium 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 calcium 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 mm 3) seen in pediatric subjects treated with fosamprenavir calcium 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 calcium. 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 calcium.Cardiac DisordersMyocardial infarction.Metabolism and Nutrition DisordersHypercholesterolemia.Nervous System DisordersOral paresthesia.Skin and Subcutaneous Tissue DisordersAngioedema.UrogenitalNephrolithiasis.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Drug InteractionsA statement to patients and healthcare providers is included on the products bottle label: ALERT: Find out about medicines that should NOT be taken with fosamprenavir calcium tablets.Fosamprenavir calcium tablets may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, particularly St. Johns wort.Advise patients receiving PDE5 inhibitors that they may be at an increased risk of PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism, and should promptly report any symptoms to their healthcare provider [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7)]. ContraceptionInstruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with fosamprenavir calcium tablets because hormonal levels may decrease, and if used in combination with fosamprenavir calcium tablets and ritonavir, liver enzyme elevations may occur [see Drug Interactions (7.2), Use in Specific Populations (8.3)]. Severe Skin ReactionsAdvise patients that skin reactions ranging from mild to severe, including Stevens-Johnson Syndrome, have been reported with fosamprenavir calcium tablets. Advise patients to discontinue fosamprenavir calcium tablets immediately for severe or life-threatening skin reactions or for moderate rashes accompanied by systemic symptoms [see Warnings and Precautions (5.2), Adverse Reactions (6)]. Sulfa AllergyAdvise patients to inform their healthcare provider if they have sulfa allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and fosamprenavir is unknown [see Warnings and Precautions (5.3)]. Hepatic ToxicityAdvise patients that it is recommended to have laboratory testing before and during therapy as patients with underlying hepatitis or or marked elevations of transaminases prior to treatment may be at increased risk for developing or worsening transaminase elevations with use of fosamprenavir calcium tablets, particularly at higher than recommended doses which should not be used. [see Warnings and Precautions (5.4)]. Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when fosamprenavir calcium tablets is started [see Warnings and Precautions (5.6)]. Increase in Body FatInform patients that an increase of body fat may occur in patients receiving protease inhibitors, including fosamprenavir calcium tablets, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)]. Lipid ElevationsAdvise patients that it is recommended to have laboratory testing before and during therapy as increases in the concentration of triglycerides and cholesterol have been reported with use of fosamprenavir calcium tablets [see Warnings and Precautions (5.8), Adverse Reactions (6)]. Pregnancy RegistryAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir calcium tablets during pregnancy [see Use in Specific Populations (8.1)]. LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)]. Missed DoseInstruct patients that if they miss dose of fosamprenavir calcium tablets, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)]. All trademarks are the property of their respective owners.Manufactured by:Ohm Laboratories Inc.New Brunswick, NJ 08901Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512June 2026 FDA-08Patient Information available at https://www.sunpharma.com/usa/products.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Fosamprenavir is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term carcinogenicity studies, fosamprenavir was administered orally for up to 104 weeks at doses of 250, 400, or 600 mg per kg per day in mice and at doses of 300, 825, or 2,250 mg per kg per day in rats. Exposures at these doses were 0.3- to 0.7-fold (mice) and 0.7- to 1.4-fold (rats) those in humans given 1,400 mg twice daily of fosamprenavir alone, and 0.2- to 0.3-fold (mice) and 0.3- to 0.7-fold (rats) those in humans given 1,400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily. Exposures in the carcinogenicity studies were 0.1- to 0.3-fold (mice) and 0.3- to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. There was an increase in hepatocellular adenomas and hepatocellular carcinomas at all doses in male mice and at 600 mg per kg per day in female mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats, and at 825 mg per kg per day and 2,250 mg per kg per day in female rats. The relevance of the hepatocellular findings in the rodents for humans is uncertain. Repeat-dose studies with fosamprenavir in rats produced effects consistent with enzyme induction, which predisposes rats, but not humans, to thyroid neoplasms. In addition, in rats only there was an increase in interstitial cell hyperplasia at 825 mg per kg per day and 2,250 mg per kg per day, and an increase in uterine endometrial adenocarcinoma at 2,250 mg per kg per day. The incidence of endometrial findings was slightly increased over concurrent controls, but was within background range for female rats. The relevance of the uterine endometrial adenocarcinoma findings in rats for humans is uncertain.Fosamprenavir was not mutagenic or genotoxic in battery of in vitroand in vivoassays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes. The effects of fosamprenavir on fertility and general reproductive performance were investigated in male (treated for weeks before mating) and female rats (treated for weeks before mating through Postpartum Day 6) that received doses of 300, 820, or 2,240 mg per kg per day. Systemic exposures (AUC 0-24 h) to amprenavir in these studies were (males) to (females) times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or similar to those seen in humans following administration of fosamprenavir in combination with ritonavir. Fosamprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Therapy-Naive Adult Trials. APV30001A 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 mm 3(range: to 1,136 cells per mm 3; 18% of subjects had CD4+ cell count of less than 50 cells per mm 3and 30% were in the range of 50 to less than 200 cells per mm 3). Baseline median HIV-1 RNA was 4.83 log 10copies per mL (range: 1.69 to 7.41 log 10copies 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)Fosamprenavir Calcium1,400 mg Twice DailyNelfinavir1,250 mg Twice Daily(n 166)(n 83)Responder 66% (57%)52% (42%)Virologic failure19%32%Rebound16%19%Never suppressed through Week 483%13%Clinical progression1%1%Death0%1%Discontinued due to adverse reactions4%2%Discontinued due to other reasons 10%10%aSubjects 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). bIncludes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons. 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 Load HIV-1 RNA (copies/mL)Fosamprenavir Calcium1,400 mg Twice DailyNelfinavir1,250 mg Twice Daily< 400 copies/mLn< 400 copies/mLn<= 100,00065%9365%46> 100,00067%7336%37Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells per mm 3in the group receiving fosamprenavir calcium and 216 cells per mm 3in the nelfinavir group. APV30002A 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 mm 3(range: to 1,055 cells per mm 3; 20% of subjects had CD4+ cell count of less than 50 cells per mm 3and 35% were in the range of 50 to less than 200 cells per mm 3). Baseline median HIV-1 RNA was 4.81 log 10copies per mL (range: 2.65 to 7.29 log 10copies 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)Fosamprenavir Calcium1,400 mg/Ritonavir 200 mg Once DailyNelfinavir1,250 mg Twice Daily(n 322)(n 327)Responder 69% (58%)68% (55%)Virologic failure6%16%Rebound5%8%Never suppressed through Week 481%8%Death1%0%Discontinued due to adverse reactions9%6%Discontinued due to other reasons 15%10%aSubjects 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). bIncludes consent withdrawn, lost to follow up, protocol violations, those with missing data, and other reasons. 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 Load HIV-1 RNA (copies/mL)Fosamprenavir Calcium1,400 mg/Ritonavir 200 mg Once DailyNelfinavir1,250 mg Twice Daily< 400 copies/mLn< 400 copies/mLn<= 100,00072%19773%194> 100,00066%12564%133Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 203 cells per mm 3in the group receiving fosamprenavir calcium and 207 cells per mm 3in the nelfinavir group. 14.2 Protease Inhibitor-Experienced Adult Trials. APV30003A randomized, open-label, multicenter trial evaluated different regimens of fosamprenavir calcium 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 mm 3(range: to 1,171 cells per mm 3). Baseline median plasma HIV-1 RNA level was 4.14 log 10copies per mL (range: 1.69 to 6.41 log 10copies per mL). The median durations of prior exposure to NRTIs were 257 weeks for subjects receiving fosamprenavir calcium/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 calcium/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 log 10copies per mL for twice-daily fosamprenavir calcium/ritonavir and -1.67 log 10copies 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 calcium/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 calcium/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 calcium/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 mm 3with twice-daily fosamprenavir calcium/ritonavir and 91 cells per mm 3with lopinavir/ritonavir. This trial was not large enough to reach definitive conclusion that fosamprenavir calcium/ritonavir and lopinavir/ritonavir are clinically equivalent.Once-daily administration of fosamprenavir calcium plus ritonavir is not recommended for protease inhibitor-experienced patients. Through Week 48, 50% and 37% of subjects receiving fosamprenavir calcium 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 calcium 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 calcium 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 calcium with ritonavir; the pharmacokinetic data from this trial did not support once-daily dosing regimen in any pediatric patient population.APV29005Fosamprenavir calcium: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 mm 3. Fosamprenavir calcium 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 mm 3and 150 cells per mm 3in protease inhibitor-naive and experienced subjects, respectively. APV20002Fifty-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 mm 3in subjects aged at least weeks to younger than months and 278 cells per mm 3in subjects aged months to years.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Fosamprenavir calcium is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.Fosamprenavir calcium is contraindicated when coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of fosamprenavir calcium and possible resistance) are listed below [see Drug Interactions (7), Clinical Pharmacology (12.3)]. The list of contraindicated drugs applies to the use of fosamprenavir calcium with or without ritonavir, unless otherwise indicated. If fosamprenavir calcium is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. Fosamprenavir calcium is contraindicated when coadministered with the following drugs: Alpha 1-adrenoreceptor antagonist: AlfuzosinAntiarrhythmics: Flecainide (with ritonavir), propafenone (with ritonavir) Antimycobacterial: RifampinAntipsychotic: Lurasidone (with ritonavir), pimozide Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovineGI motility agent: CisaprideHerbal product: St. Johns wort Hypericum perforatum) Lipid modifying agents: Lomitapide, lovastatin, simvastatinNon-nucleoside reverse transcriptase inhibitor: DelavirdinePDE5 inhibitor: Sildenafil (Revatio) (for treatment of pulmonary arterial hypertension)Sedative/hypnotics: Midazolam, triazolam Fosamprenavir calcium is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome) to any of the components of this product or to amprenavir.. Fosamprenavir calcium is contraindicated when coadministered with drugs that are highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of fosamprenavir calcium and possible resistance) are listed below [see Drug Interactions (7), Clinical Pharmacology (12.3)]. The list of contraindicated drugs applies to the use of fosamprenavir calcium with or without ritonavir, unless otherwise indicated. If fosamprenavir calcium is coadministered with ritonavir, reference should be made to the full prescribing information for ritonavir for additional contraindications. Fosamprenavir calcium is contraindicated when coadministered with the following drugs: Alpha 1-adrenoreceptor antagonist: AlfuzosinAntiarrhythmics: Flecainide (with ritonavir), propafenone (with ritonavir) Antimycobacterial: RifampinAntipsychotic: Lurasidone (with ritonavir), pimozide Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovineGI motility agent: CisaprideHerbal product: St. Johns wort Hypericum perforatum) Lipid modifying agents: Lomitapide, lovastatin, simvastatinNon-nucleoside reverse transcriptase inhibitor: DelavirdinePDE5 inhibitor: Sildenafil (Revatio) (for treatment of pulmonary arterial hypertension)Sedative/hypnotics: Midazolam, triazolam Alpha 1-adrenoreceptor antagonist: Alfuzosin. Antiarrhythmics: Flecainide (with ritonavir), propafenone (with ritonavir) Antimycobacterial: Rifampin. Antipsychotic: Lurasidone (with ritonavir), pimozide Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine. GI motility agent: Cisapride. Herbal product: St. Johns wort Hypericum perforatum) Lipid modifying agents: Lomitapide, lovastatin, simvastatin. Non-nucleoside reverse transcriptase inhibitor: Delavirdine. PDE5 inhibitor: Sildenafil (Revatio) (for treatment of pulmonary arterial hypertension). Sedative/hypnotics: Midazolam, triazolam. Hypersensitivity to fosamprenavir calcium or amprenavir (e.g., Stevens-Johnson syndrome). (4)Drugs highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. (4)Review ritonavir contraindications when used in combination. (4). Hypersensitivity to fosamprenavir calcium or amprenavir (e.g., Stevens-Johnson syndrome). (4). Drugs highly dependent on cytochrome P450 (CYP)3A4 for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. (4). Review ritonavir contraindications when used in combination. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Fosamprenavir calcium, USP is prodrug of amprenavir, an inhibitor of HIV protease. The chemical name of fosamprenavir calcium, USP is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl](isobutyl)amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium salt. Fosamprenavir calcium, USP is single stereoisomer with the (3S)(1S,2R) configuration. It has molecular formula of C25H34CaN3O9PS and molecular weight of 623.7. It has the following structural formula:Fosamprenavir calcium, USP is white to cream color solid which is soluble in methanol.Fosamprenavir calcium tablets, USP are available for oral administration in strength of 700 mg of fosamprenavir as fosamprenavir calcium, USP (equivalent to approximately 600 mg of amprenavir). Each 700 mg tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone. The tablet coating contains the inactive ingredients ethylcellulose, ferric oxide red, hypromellose, talc, and titanium dioxide. The imprinting ink contains the inactive ingredients ferric oxide black, propylene glycol, and shellac.Meets USP dissolution test 3.. Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Therapy-Naive Adults: Fosamprenavir calcium tablets 1,400 mg twice daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2)Protease Inhibitor-Experienced Adults: Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2)Pregnant Patients: Fosamprenavir calcium tablets 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 calcium /ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). (2.2)Pediatric 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)Hepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. (2.4)Dosing ConsiderationsFosamprenavir calcium tablets may be taken with or without food. (2.1)Fosamprenavir Calcium Oral Suspension: Adults should take without food; pediatric patients should take with food. (2.1). Therapy-Naive Adults: Fosamprenavir calcium tablets 1,400 mg twice daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily; fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily; fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2). Protease Inhibitor-Experienced Adults: Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. (2.2). Pregnant Patients: Fosamprenavir calcium tablets 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 calcium /ritonavir 700 mg/100 mg prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). (2.2). Pediatric 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). Hepatic Impairment: Recommended adjustments for patients with mild, moderate, or severe hepatic impairment. (2.4). Fosamprenavir calcium tablets may be taken with or without food. (2.1). Fosamprenavir Calcium Oral Suspension: Adults should take without food; pediatric patients should take with food. (2.1). 2.1 General Dosing Information. Fosamprenavir calcium tablets may be taken with or without food.Adults should take fosamprenavir calcium oral suspension without food. Pediatric patients should take fosamprenavir calcium oral suspension with food [see Clinical Pharmacology (12.3)]. If emesis occurs within 30 minutes after dosing, re-dosing of fosamprenavir calcium oral suspension should occur. Higher-than-approved dose combinations of fosamprenavir calcium tablets plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)]. When fosamprenavir calcium tablets are used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.. 2.2 Adults. Therapy-Naive AdultsFosamprenavir calcium tablets 1,400 mg twice daily (without ritonavir).Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily.Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. Dosing of fosamprenavir calcium tablets 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 AdultsFosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily.PregnancyFosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 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 calcium /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 calcium tablets (with or without ritonavir) in pregnancy are not available. Fosamprenavir calcium tablets 1,400 mg twice daily (without ritonavir).. Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 200 mg once daily.. Fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily.. Dosing of fosamprenavir calcium tablets 1,400 mg once daily plus ritonavir 100 mg once daily is supported by pharmacokinetic data [see Clinical Pharmacology (12.3)]. Dosing of fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily is supported by pharmacokinetic and safety data [see Clinical Pharmacology (12.3)]. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily.. Fosamprenavir calcium tablets 700 mg twice daily plus ritonavir 100 mg twice daily. Dosing of fosamprenavir calcium tablets 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 calcium /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 calcium tablets (with or without ritonavir) in pregnancy are not available. Dosing of fosamprenavir calcium tablets 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 calcium /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 calcium tablets (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 calcium 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 Calcium 45 mg/kg plus ritonavir mg/kg 11 kg < 15 kgFosamprenavir Calcium 30 mg/kg plus ritonavir mg/kg 15 kg < 20 kgFosamprenavir Calcium 23 mg/kg plus ritonavir mg/kg >= 20 kgFosamprenavir Calcium 18 mg/kg plus ritonavir mg/kg aWhen dosing with ritonavir, do not exceed the adult dose of fosamprenavir calcium 700 mg/ritonavir 100 mg twice-daily dose. Alternatively, protease inhibitor-naive children aged years and older can be administered fosamprenavir calcium (without ritonavir) 30 mg per kg twice daily.Fosamprenavir calcium 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:do not support once-daily dosing of fosamprenavir calcium alone or in combination with ritonavir [see Clinical Studies (14.3)]. do not support administration of fosamprenavir calcium alone or in combination with ritonavir for protease inhibitor-experienced children younger than months [see Clinical Pharmacology (12.3)]. do not support twice-daily dosing of fosamprenavir calcium without ritonavir in pediatric patients younger than years [see Clinical Pharmacology (12.3)]. Other Dosing ConsiderationsWhen 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.When 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.. do not support once-daily dosing of fosamprenavir calcium alone or in combination with ritonavir [see Clinical Studies (14.3)]. do not support administration of fosamprenavir calcium alone or in combination with ritonavir for protease inhibitor-experienced children younger than months [see Clinical Pharmacology (12.3)]. do not support twice-daily dosing of fosamprenavir calcium without ritonavir in pediatric patients younger than years [see Clinical Pharmacology (12.3)]. When 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.. When 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 calcium tablets 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 calcium tablets 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 calcium tablets 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Fosamprenavir calcium tablets, USP, 700 mg, are pink colored, coated, oval-shaped tablets with RJ47 imprinted on one side with black ink and plain on the other side. 700 mg tablets (3). 700 mg tablets (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration of fosamprenavir calcium with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3)Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3)Coadministration of fosamprenavir calcium or fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7)Coadministration of fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP2D6. (7). Coadministration of fosamprenavir calcium with drugs that induce CYP3A4 may decrease amprenavir (active metabolite) concentrations leading to potential loss of virologic activity. (7, 12.3). Coadministration with drugs that inhibit CYP3A4 may increase amprenavir concentrations. (7, 12.3). Coadministration of fosamprenavir calcium or fosamprenavir calcium and ritonavir may result in clinically significant interactions with drugs metabolized by CYP3A4. (7). Coadministration of fosamprenavir calcium 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 calcium and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of fosamprenavir calcium and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects.The potential for drug interactions with fosamprenavir calcium changes when fosamprenavir calcium 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 calcium is coadministered with ritonavir. Because ritonavir is CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with fosamprenavir calcium 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 calcium 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 calcium 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 calcium: Amprenavir(predicted)<-> or Boceprevir(predicted)Fosamprenavir calcium /ritonavir:Amprenavir(predicted)Boceprevir(predicted)Coadministration of fosamprenavir calcium or fosamprenavir calcium/ ritonavir and boceprevir is not recommended.HCV protease inhibitor:SimeprevirFosamprenavir calcium:<-> Amprenavir(predicted) or Simeprevir(predicted)Fosamprenavir calcium /ritonavir:<->Amprenavir(predicted)Simeprevir(predicted)Coadministration of fosamprenavir calcium or fosamprenavir calcium/ritonavir and simeprevir is not recommended.HCV protease inhibitor:Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)Fosamprenavir calcium:Amprenavir(predicted) or <->Paritaprevir(predicted)Fosamprenavir calcium /ritonavir: or <->Amprenavir(predicted)Paritaprevir(predicted)Appropriate doses of the combinations with respect to safety and efficacy have not been established.Fosamprenavircalcium 1,400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir.Coadministration of Fosamprenavircalcium /ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.Non-nucleoside reverse transcriptase inhibitor:Delavirdine Fosamprenavir calcium: Amprenavir DelavirdineCoadministration is contraindicated as it may lead to loss of virologic response and possible resistance to delavirdine [see Contraindications (4)]. Fosamprenavir calcium/ritonavir: AmprenavirDelavirdineNon-nucleoside reverse transcriptase inhibitor:Efavirenz Fosamprenavir calcium: AmprenavirFosamprenavir calcium/ritonavir: AmprenavirAppropriate doses of the combinations with respect to safety and efficacy have not been established.An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir calcium /ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with Fosamprenavir calcium plus ritonavir twice daily.Non-nucleoside reverse transcriptase inhibitor:Nevirapine aFosamprenavir calcium: Amprenavir NevirapineCoadministration of nevirapine and fosamprenavir calcium without ritonavir is not recommended.Fosamprenavir calcium/ritonavir: Amprenavir NevirapineNo dosage adjustment required when nevirapine is administered with fosamprenavir calcium/ritonavir twice daily.The combination of nevirapine administered with fosamprenavir calcium/ritonavir once-daily regimen has not been studied.HIV protease inhibitor:Atazanavir Fosamprenavir calcium:Interaction has not been evaluated.Appropriate doses of the combinations with respect to safety and efficacy have not been established.Fosamprenavir calcium/ritonavir: Atazanavir<-> AmprenavirHIV protease inhibitors:Indinavir a, nelfinavir Fosamprenavir calcium: AmprenavirEffect on indinavir and nelfinavir is not well established.Fosamprenavir calcium/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 LopinavirAn 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 calcium: AmprenavirEffect on saquinaviris not well established.Fosamprenavir calcium/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 calcium: Amprenavir RaltegravirFosamprenavir calcium/ritonavir: Amprenavir RaltegravirAppropriate doses of the combination with respect to safety and efficacy have not been established.HIV integrase inhibitor:Dolutegravir aFosamprenavir calcium /ritonavir:Dolutegravir The recommended dose of dolutegravir is 50 mg twice daily when coadministered with Fosamprenavircalcium /ritonavir.Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.HIV CCR5 co-receptor antagonist:Maraviroc Fosamprenavir calcium/ritonavir: Amprenavir MaravirocNo dosage adjustment required for fosamprenavir calcium /ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with fosamprenavir calcium/ritonavir. Fosamprenavir calcium should be given with ritonavir when coadministered with maraviroc.Other AgentsAlpha 1-adrenoreceptor antagonist:AlfuzosinAlfuzosinCoadministration is contraindicated due to potential hypotension [see Contraindications (4)]. Antacid:MAALOX TCAmprenavirUse with caution when administered at the same time. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations.Staggered coadministration of antacids and fosamprenavir calcium has not been evaluated.Antiarrhythmics:Amiodarone, disopyramide, lidocaine (systemic), and quinidineFlecainide, propafenone AntiarrhythmicsAntiarrhythmicsTherapeutic concentration monitoring, if available, is recommended for antiarrhythmics.Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias if fosamprenavir calcium 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 calcium: AmprenavirUse with caution. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.Phenytoin Fosamprenavir calcium/ritonavir: Amprenavir PhenytoinPlasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in fosamprenavir calcium/ritonavir dose is recommended.Antidepressant:Paroxetine, trazodone ParoxetineAny paroxetine dose adjustment shouldbe 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 calcium, the combination should be used with caution and lower dose of trazodone should be considered.Antifungals:Ketoconazole a, itraconazole Ketoconazole ItraconazoleIncrease monitoring for adverse events.Fosamprenavir calcium:Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day.Fosamprenavir calcium/ritonavir:High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.Anti-gout:Colchicine ColchicinePatients with renal or hepatic impairment should not be given colchicine with fosamprenavir calcium/ritonavir.Fosamprenavir calcium/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 calcium 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 metaboliteA complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia.Fosamprenavir calcium:A dosage reduction of rifabutin by at least half the recommended dose is required.Fosamprenavir calcium/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:Rifampin aAmprenavirCoadministration is contraindicated as it may lead to loss of virologic response and possible resistance to Fosamprenavir calcium or to the class of protease inhibitors [see Contraindications (4)]. Antineoplastics:Dasatinib, nilotinib, ibrutinib, vinblastine, everolimus AntineoplasticsFosamprenavir calcium or fosamprenavir calcium /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:LurasidonePimozideQuetiapineLurasidonePimozideQuetiapineFosamprenavir calcium:If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.Fosamprenavir calcium /ritonavir:Use of lurasidone is contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4)]. Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Fosamprenavir calcium /ritonavir:Initiation of fosamprenavir calcium 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 calcium with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines:Alprazolam, clorazepate, diazepam, flurazepam BenzodiazepinesClinical significance is unknown. decrease in benzodiazepine dose may be needed.Calcium channel blockers:Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine Calcium channel blockersUse with caution. Clinical monitoring of patients is recommended.Corticosteroid:Dexamethasone AmprenavirUse with caution. Fosamprenavir calcium may be less effective due to decreased amprenavir plasma concentrations.Endothelin-receptor antagonist:Bosentan BosentanCoadministration of bosentan in patients on fosamprenavir calcium:In patients who have been receiving fosamprenavir calcium for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of fosamprenavir calcium in patients on bosentan:Discontinue use of bosentan at least 36 hours prior to initiation of fosamprenavir calcium.After at least 10 days following the initiation of fosamprenavir calcium, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Ergot derivatives:Dihydroergotamine,ergonovine, ergotamine,methylergonovineErgot 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:CisaprideCisaprideCoadministration 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 calcium or to the class of protease inhibitors [see Contraindications (4)]. Histamine 2-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine Fosamprenavir calcium: AmprenavirFosamprenavir calcium/ritonavir:Interaction not evaluatedUse with caution. Fosamprenavir calcium 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 SalmeterolConcurrent administration of salmeterol with fosamprenavir calcium 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 calcium: FluticasoneUse with caution. Consider alternatives to fluticasone, particularly for long-term use.Fosamprenavir calcium/ritonavir: FluticasoneMay 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 calcium/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: Atorvastatin Lovastatin, simvastatinOther lipid modifying agents: LomitapideAtorvastatinLovastatinSimvastatinLomitapideTitrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see Contraindications (4)]. Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases.Narcotic analgesic:MethadoneFentanyl MethadoneFentanylData suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.Careful monitoring of therapeutic effects and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended.Oral contraceptives:Ethinyl estradiol/norethindrone Alternative methods of non-hormonal contraception are recommended.Fosamprenavir calcium: Amprenavir Ethinyl estradiolMay lead to loss of virologic response. Fosamprenavir calcium/ritonavir: Ethinyl estradiolIncreased risk of transaminase elevations. No data are available on the use of fosamprenavir calcium/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.PDE5 inhibitors:Sildenafil, tadalafil,vardenafil Sildenafil Tadalafil VardenafilMay 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):oUse of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH. safe and effective dose has not been established when used with fosamprenavir calcium. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope) [see Contraindications (4)].o The following dose adjustments are recommended for use of tadalafil (ADCIRCA (R)) with fosamprenavir calcium: Coadministration of ADCIRCA in patients on fosamprenavir calcium:In patients receiving fosamprenavir calcium 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 calcium in patients on ADCIRCA:Avoid use of ADCIRCA during the initiation of fosamprenavir calcium. Stop ADCIRCA at least 24 hours prior to starting fosamprenavir calcium. After at least one week following the initiation of fosamprenavir calcium, 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 calcium: 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 calcium/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 a, lansoprazole, omeprazole, pantoprazole, rabeprazole Fosamprenavir calcium:<-> Amprenavir EsomeprazoleProton pump inhibitors can be administered at the same time as dose of fosamprenavir calcium with no change in plasma amprenavir concentrations.Fosamprenavir calcium/ritonavir:<-> Amprenavir<-> EsomeprazoleSedative/hypnotics:Midazolam, triazolamMidazolamTriazolamCoadministration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. Tricyclicantidepressants:Amitriptyline, imipramine TricyclicsTherapeutic concentration monitoring is recommended for tricyclic antidepressants.aSee Clinical Pharmacology (12.3) Tables 10, 11, 12, or 13 for magnitude of interaction.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of fosamprenavir calcium 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Fosamprenavir calcium tablets, USP, 700 mg, are pink colored, coated, oval-shaped tablets with RJ47imprinted on one side with black ink and plain on the other side. They are supplied as follows- NDC 63304-583-30 Bottles of 30 with child-resistant closureNDC 63304-583-60 Bottles of 60 with child-resistant closureNDC 63304-583-01 Bottles of 100Store at 20 to 25 (68 to 77 F) [See USP Controlled Room Temperature].Keep bottle tightly closed. Protect from moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Fosamprenavir calcium tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.The following points should be considered when initiating therapy with fosamprenavir calcium tablets plus ritonavir in protease inhibitor-experienced patients:The protease inhibitor-experienced patient trial was not large enough to reach definitive conclusion that fosamprenavir calcium tablets plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)]. Once-daily administration of fosamprenavir calcium tablets plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.2, 2.3), Clinical Studies (14.2, 14.3)]. Dosing of fosamprenavir calcium tablets plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than months [see Clinical Pharmacology (12.3)]. The protease inhibitor-experienced patient trial was not large enough to reach definitive conclusion that fosamprenavir calcium tablets plus ritonavir and lopinavir plus ritonavir are clinically equivalent [see Clinical Studies (14.2)]. Once-daily administration of fosamprenavir calcium tablets plus ritonavir is not recommended for adult protease inhibitor-experienced patients or any pediatric patients [see Dosage and Administration (2.2, 2.3), Clinical Studies (14.2, 14.3)]. Dosing of fosamprenavir calcium tablets plus ritonavir is not recommended for protease inhibitor-experienced pediatric patients younger than months [see Clinical Pharmacology (12.3)]. Fosamprenavir calcium tablets are HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In long-term carcinogenicity studies, fosamprenavir was administered orally for up to 104 weeks at doses of 250, 400, or 600 mg per kg per day in mice and at doses of 300, 825, or 2,250 mg per kg per day in rats. Exposures at these doses were 0.3- to 0.7-fold (mice) and 0.7- to 1.4-fold (rats) those in humans given 1,400 mg twice daily of fosamprenavir alone, and 0.2- to 0.3-fold (mice) and 0.3- to 0.7-fold (rats) those in humans given 1,400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily. Exposures in the carcinogenicity studies were 0.1- to 0.3-fold (mice) and 0.3- to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. There was an increase in hepatocellular adenomas and hepatocellular carcinomas at all doses in male mice and at 600 mg per kg per day in female mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats, and at 825 mg per kg per day and 2,250 mg per kg per day in female rats. The relevance of the hepatocellular findings in the rodents for humans is uncertain. Repeat-dose studies with fosamprenavir in rats produced effects consistent with enzyme induction, which predisposes rats, but not humans, to thyroid neoplasms. In addition, in rats only there was an increase in interstitial cell hyperplasia at 825 mg per kg per day and 2,250 mg per kg per day, and an increase in uterine endometrial adenocarcinoma at 2,250 mg per kg per day. The incidence of endometrial findings was slightly increased over concurrent controls, but was within background range for female rats. The relevance of the uterine endometrial adenocarcinoma findings in rats for humans is uncertain.Fosamprenavir was not mutagenic or genotoxic in battery of in vitroand in vivoassays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes. The effects of fosamprenavir on fertility and general reproductive performance were investigated in male (treated for weeks before mating) and female rats (treated for weeks before mating through Postpartum Day 6) that received doses of 300, 820, or 2,240 mg per kg per day. Systemic exposures (AUC 0-24 h) to amprenavir in these studies were (males) to (females) times higher than exposures in humans following administration of the MRHD of fosamprenavir alone or similar to those seen in humans following administration of fosamprenavir in combination with ritonavir. Fosamprenavir did not impair mating or fertility of male or female rats and did not affect the development and maturation of sperm from treated rats.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In healthy volunteer repeat-dose pharmacokinetic trial evaluating high-dose combinations of fosamprenavir calcium plus ritonavir, an increased frequency of Grade 2/3 ALT elevations (greater than 2.5 ULN) was observed with fosamprenavir calcium 1,400 mg twice daily plus ritonavir 200 mg twice daily (4 of 25 subjects). Concurrent Grade 1/2 elevations in AST (greater than 1.25 ULN) were noted in of these subjects. These transaminase elevations resolved following discontinuation of dosing.There is no known antidote for fosamprenavir calcium. It is not known whether amprenavir can be removed by peritoneal dialysis or hemodialysis, although it is unlikely as amprenavir is highly protein bound. If overdosage occurs, the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL. NDC 63304-583-60Fosamprenavir Calcium Tablets700 mgALERT: Find out about medicines that should NOT be taken with Fosamprenavir Calcium Tablets.Note to Pharmacist: Do not cover ALERT box with pharmacy label.Rx only60 Tablets ohm (R) fosam-label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety, pharmacokinetic profile, and virologic and immunologic responses of fosamprenavir calcium 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 calcium is not recommended in protease inhibitor-experienced pediatric patients younger than months. The pharmacokinetics, safety, tolerability, and efficacy of fosamprenavir calcium 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 calcium 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetic properties of amprenavir after administration of fosamprenavir calcium, 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 calcium (with and without concomitant ritonavir) are shown in Table 7.Table 7. Geometric Mean (95% CI) Steady-State Plasma Amprenavir Pharmacokinetic Parameters in AdultsRegimenC max (mcg/mL)T max (hours) AUC 24 (mcgoh/mL)C tau (mcg/mL)Fosamprenavir calcium 1,400 mg Twice Daily(n 22) 4.82(4.06 to 5.72)1.3(0.8to 4)33 (27.6to 39.2)0.35(0.27to 0.46)Fosamprenavir calcium 1,400 mg Once Daily plus Ritonavir 200 mg Once Daily (n 22) 7.24(6.32 to 8.28)2.1(0.8t 5)69.4(59.7 to 80.8)1.45(1.16 to 1.81)Fosamprenavir calcium 1,400 mg Once Daily plus Ritonavir 100 mg Once Daily (n 36) 7.93(7.25 to 8.68)1.5(0.75 to 5)66.4(61.1 to 72.1)0.86(0.74 to 1.01)Fosamprenavir calcium 700 mg Twice Daily plus Ritonavir 100 mg Twice Daily (n 24) 6.08(5.38 to 6.86)1.5(0.75 to 5)79.2 (69 to 90.6)2.12(1.77 to 2.54)aData shown are median (range). bC tauis the concentration at the end of the dose interval. cHIV-infected adults. dAUC 24was calculated from AUC 12summary data 2. eHealthy adults. 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 EC 50Values against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) AbsorptionAfter administration of single dose of fosamprenavir calcium to HIV-1-infected subjects, the time to peak amprenavir concentration (T max) occurred between 1.5 and hours (median 2.5 hours). The absolute oral bioavailability of amprenavir after administration of fosamprenavir calcium 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 maxof 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 AbsorptionAdministration 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 max, max, or AUC 0- [see Dosage and Administration (2)]. Administration of single 1,400 mg dose of fosamprenavir calcium oral suspension 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 46% reduction in max, 0.72-hour delay in max, and 28% reduction in amprenavir AUC 0-. DistributionIn vitro, amprenavir is approximately 90% bound to plasma proteins, primarily to alpha 1-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. MetabolismAfter 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.EliminationExcretion 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 PopulationsPatients with Hepatic Impairment: The pharmacokinetics of amprenavir have been studied after the administration of fosamprenavir calcium in combination with ritonavir to adult HIV-1-infected subjects with mild, moderate, and severe hepatic impairment. Following weeks of dosing with fosamprenavir calcium 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 max) ranged between decrease of -7% to an increase of 57% while the unbound fraction at the end of the dosing interval (C min) 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 calcium (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 calcium in non-pregnant adults and lower concentrations compared with fosamprenavir calcium (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 calcium with RitonavirPharmacokinetic ParameterFosamprenavir calcium 700 mg Twice Daily plus Ritonavir 100 mg Twice DailySecond Trimester(n 6)Third Trimester(n 9)Postpartum(n 9)AUC 12(mcgoh/mL) 26.0(19.5, 34.6)30.1(21.6, 41.9)39.9(31.9, 50.1)AUC 24(mcgoh/mL) 52.0(39.0, 69.2)60.2(43.2, 83.8)79.8(63.8, 100.2)C max(mcg/mL) 4.19(3.19, 5.51)5.36(3.98, 7.22)6.65(5.24, 8.44)C tau(mcg/mL) 1.31(0.97, 1.77)1.34(0.95, 1.89)2.03(1.46, 2.83)aAUC 24was calculated from AUC 12summary data 2. bC taurepresents the concentration at the end of the dose interval. 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 calcium without ritonavir was administered as 30 or 40 mg per kg twice daily to children aged to years. Fosamprenavir calcium with ritonavir was administered as fosamprenavir calcium 30 mg per kg plus ritonavir mg per kg once daily to children aged to 18 years and as fosamprenavir calcium 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 calcium.The pharmacokinetics of fosamprenavir calcium oral suspension in protease inhibitor-naive infants younger than months (n 9) receiving fosamprenavir calcium 45 mg per kg plus ritonavir 10 mg per kg twice daily generally demonstrated lower AUC 12and minthan adults receiving twice-daily fosamprenavir calcium 700 mg plus ritonavir 100 mg, the dose recommended for protease-experienced adults. The mean steady-state amprenavir AUC 12, max, and minwere 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 calcium alone (without ritonavir) in pediatric subjects younger than years was not studied. Pharmacokinetic parameters for fosamprenavir calcium 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 Calcium with RitonavirWeightRecommended Dosage RegimenC max AUC 24 min n(mcg/mL)n(mcgoh/mL)n(mcg/mL)< 11 kgFosamprenavir calcium 45 mg/kg plus Ritonavir mg/kg twice daily126 (3.88, 9.29)1257.3(34.1, 96.2)271.65(1.22, 2.24)11 kg < 15 kgFosamprenavir calcium 30 mg/kg plus Ritonavir mg/kg twice dailyNot studied 15 kg < 20 kgFosamprenavir calcium 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 calcium 18 mg/kg plus Ritonavir mg/kg twice daily136.24(5.01, 7.77)1297.9(77, 124)232.54(2.11, 3.06)>= 39 kgFosamprenavir calcium 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)aRecommended dose for pediatric patients weighing 11 kg to less than 15 kg is based on population pharmacokinetic analysis. Subjects aged to younger than years receiving fosamprenavir calcium 30 mg per kg twice daily without ritonavir achieved geometric mean (95% CI) amprenavir max(n 9), AUC 12(n 9), and min(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 calcium 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 calcium do not differ between males and females. Racial Groups:The pharmacokinetics of amprenavir after administration of fosamprenavir calcium 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 calcium and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration on AUC, max, and minvalues are summarized in Table 10 (effect of other drugs on amprenavir) and Table 12 (effect of fosamprenavir calcium on other drugs). In addition, since fosamprenavir calcium 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 Calcium in the Presence of the Coadministered Drug(s)Coadministered Drug(s) and Dose(s)Dose of Fosamprenavir Calcium n% Change in Amprenavir Pharmacokinetic Parameters (90% CI)C max AUCC min Antacid (MAALOX TC)30 mL single dose1,400-mgsingle dose30 35( 24 to 42) 18( to 26) 14( to 39)Atazanavir300 mg once daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 10 days22<-><-><->Atorvastatin10 mg once daily for days1,400 mg twice daily for weeks16 18( 34 to 1) 27( 41 to 12) 12( 27 to 6)Atorvastatin10 mg once daily for days700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-><->Efavirenz600 mg once daily for weeks1,400 mg once daily plus ritonavir 200 mg once daily for weeks16<-> 13( 30 to 7) 36( to 56)Efavirenz600 mg once daily plus additional ritonavir 100 mg once daily for weeks1,400 mg once daily plus ritonavir 200 mg once daily for weeks16 18( to 38) 11(0 to 24)<->Efavirenz600 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks16<-><-> 17( to 29)Esomeprazole20 mg once daily for weeks1,400 mg twice daily for weeks25<-><-><->Esomeprazole20 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><-><->Ethinyl estradiol/norethindrone0.035 mg/0.5 mg once daily for 21 days700 mg twice daily plus ritonavir b100 mg twice daily for 21 days 25<-> <-> <-> Ketoconazole 200 mg once daily for days700 mg twice daily plus ritonavir 100 mg twice daily for days15<-><-><->Lopinavir/ritonavir533 mg/133 mg twice daily1,400 mg twice daily for weeks18 13 26 42 Lopinavir/ritonavir400 mg/100 mg twice daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks18 58( 42 to 70) 63( 51 to 72) 65( 54 to 73)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir100 mg twice daily for20 days14 34( 25 to 41) 35( 29 to 41) 36( 27 to 43)Maraviroc300 mg once daily for 10 days1,400 mg once dailyplus ritonavir100 mg once daily for20 days14 29( 20 to 38)30(23 to 36) 15(3 to 25)Methadone70 to 120 mg once daily for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks19<-> <-> <-> Nevirapine200 mg twice daily for weeks 1,400 mg twice daily for weeks17 25( 37 to 10) 33( 45 to 20) 35( 50 to 15)Nevirapine200 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)Phenytoin300 mg once daily for 10 days700 mg twice daily plus ritonavir 100 mg twice daily for 10 days13<-> 20( to 34) 19( to 33)Raltegravir400 mg twice daily for 14 days1,400 mg twice daily for 14 days (fasted)14 27( 46 to <->) 36( 53 to 13) 43 ( 59 to 21)1,400 mg twice daily for 14 days 14 15( 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)14 14( 39 to 20) 17( 38 to 12) 20 ( 45 to 17)700 mg twice daily plus ritonavir 100 mg twice daily for 14 days12 25( 42 to 2) 25( 44 to <->) 33 ( 52 to 7)Raltegravir400 mg twice daily. for 14 days1,400 mg once daily plus ritonavir 100 mg once daily for 14 days (fasted)13 18( 34 to <->) 24( 41 to <->) 50 ( 64 to 31)1,400 mg once daily plus ritonavir 100 mg once daily for 14 days 14 27( to 62) 13( to 38) 17 ( 45 to 26)Ranitidine300 mg single dose (administered hour before fosamprenavir)1,400 mg single dose30 51( 43 to 58) 30( 22 to 37)<->( 19 to 21)Rifabutin150 mg every other day for weeks700 mg twice daily plus ritonavir 100 mg twice daily for weeks15 36 ( 18 to 55) 35 ( 17 to 56) 17 ( to 39)Tenofovir300 mg once daily for to 48 weeks700 mg twice daily plus ritonavir 100 mg twice daily for to 48 weeks45NANA<-> Tenofovir300 mg once daily for to 48 weeks1,400 mg once daily plus ritonavir 200 mg once daily for to 48 weeks60NANA<-> aConcomitant medication is also shown in this column where appropriate. bRitonavir max, AUC, and minincreased by 63%, 45%, and 13%, respectively, compared with historical control. cCompared with historical control. dSubjects were receiving fosamprenavir calcium/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir calcium/ritonavir. eCompared with fosamprenavir calcium 700 mg/ritonavir 100 mg twice daily for weeks. fSubjects were receiving nevirapine for at least 12 weeks prior to trial. gC last(C 12 hor 24 h). hDoses of fosamprenavir calcium and raltegravir were given with food on pharmacokinetic sampling days and without regard to food all other days. iN 18 for min. jCompared with parallel control group. Increase; Decrease; <-> No change or less than or equal to 10%), NA Not applicable.Table 11. Drug Interactions: Pharmacokinetic Parameters for Amprenavir after Administration of Agenerase in the Presence of the Coadministered Drug(s)Coadministered Drug(s) and Dose(s)Dose ofAgenerase n% Change in Amprenavir Pharmacokinetic Parameters(90% CI)C max AUCC min Abacavir300 mg twice daily for to weeks 900 mg twice dailyfor to weeks4<-> <-> <-> Clarithromycin500 mg twice daily for days 1,200 mg twice dailyfor days12 15( to 31) 18( to 29) 39( 31 to 47)Delavirdine600 mg twice daily for 10 days 600 mg twice dailyfor 10 days9 40 130 125 Ethinyl estradiol/norethindrone0.035 mg/1 mg for cycle 1,200 mg twice dailyfor 28 days10<-> 22( 35 to 8) 20( 41 to 8)Indinavir800 mg times day for weeks (fasted) 750 or 800 mg times day for weeks (fasted)9 18( 13 to 58) 33( to 73) 25( 27 to 116)Ketoconazole400-mg single dose 1,200-mgsingle dose12 16( 25 to 6) 31( 20 to 42)NALamivudine150-mg single dose 600-mgsingle dose11<-><->NAMethadone44 to 100 mg once daily for 30 days1,200 mg mg twice dailyfor 10 days16 27 30 25 Nelfinavir750 mg times day for weeks (fed) 750 or 800 mg times day for weeks (fed)6 14( 38 to 20)<-> 189( 52 to 448)Rifabutin300 mg once daily for 10 days 1,200 mg twice dailyfor 10 days5<-> 15( 28 to 0) 15( 38 to 17)Rifampin300 mg once daily for days 1,200 mg twice dailyfor days11 70( 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)7 37( 54 to 14) 32( 49 to 9) 14( 52 to 54)Zidovudine300-mg single dose 600-mgsingle dose12<-> 13( to 31)NAaCompared with parallel control group. bMedian percent change; confidence interval not reported. cCompared with historical data. Increase; Decrease; <-> No change or less than 10%); NA C minnot calculated for single-dose trial. Table 12. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Fosamprenavir CalciumCoadministered Drug(s)and Dose(s)Dose ofFosamprenavir Calcium n% Change in Pharmacokinetic Parameters of Coadministered Drug(90% CI)C max AUCC min Atazanavir300 mg once daily for 10 days b700 mg twice daily plus ritonavir 100 mg twice daily for 10 days21 24( 39 to 6) 22( 34 to 9)<->Atorvastatin10 mg once daily for days 1,400 mg twice daily for weeks16 304( 205 to 437) 130( 100 to 164) 10( 27 to 12)Atorvastatin10 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice daily for weeks16 184( 126 to 257) 153( 115 to 199) 73( 45 to 108)Esomeprazole20 mg once daily for weeks 1,400 mg twice daily for weeks25<-> 55( 39 to 73)NDEsomeprazole20 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks23<-><->NDEthinyl estradiol 0.035 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days25 28( 21 to 35) 37( 30 to 42)NDDolutegravir 50 mg once daily700 mg twice daily plus ritonavir 100 mg twice daily1224 (8 to 37)35 (22 to 46)49 (37 to 59)Ketoconazole 200 mg once daily for days 700 mg twice daily plus ritonavir 100 mg twice dailyfor days15 25( to 56) 169( 108 to 248)NDLopinavir/ritonavir 533 mg/133 mg twice daily for weeks 1,400 mg twice daily for weeks18<-> <-> <-> Lopinavir/ritonavir 400 mg/100 mg twice daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks18 30( 15 to 47) 37( 20 to 55) 52( 28 to 82)Maraviroc300 mg twice daily for 10 days700 mg twice daily plus ritonavir100 mg twice daily for20 days14 52( 27 to 82) 149( 119 to 182) 374( 303 to 457)Maraviroc300 mg once daily for 10 days1,400 mg once dailyplus ritonavir100 mg once daily for20 days14 45( 20 to 74) 126( 99 to 158) 80( 53 to 113)Methadone70 to 120 mg once daily for weeks 700 mg twice daily plus ritonavir 100 mg twice daily for weeks19R-Methadone (active) 21 ( 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)Nevirapine200 mg twice daily for weeks 1,400 mg twice daily for weeks17 25( 14 to 37) 29( 19 to 40) 34( 20 to 49)Nevirapine200 mg twice daily for weeks h700 mg twice daily plus ritonavir 100 mg twice daily for weeks17 13( to 24) 14( to 24) 22( to 35)Norethindrone 0.5 mg once daily for 21 days 700 mg twice daily plus ritonavir 100 mg twice daily for 21 days25 38( 32 to 44) 34( 30 to 37) 26( 20 to 32)Phenytoin300 mg once daily for 10 days 700 mg twice daily plus ritonavir 100 mg twice daily. for 10 days14 20( 12 to 27) 22( 17 to 27) 29( 23 to 34)Rifabutin150 mg every other day for weeks i700 mg twice daily plus ritonavir 100 mg twice daily for weeks15 14( 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 metaboliteNA 64( 46 to 84)NARosuvastatin10 mg single dose700 mg twice dailyplus ritonavir100 mg twice dailyfor7 days( 45)( 8) NAaConcomitant medication is also shown in this column where appropriate. bComparison arm of atazanavir 300 mg once daily plus ritonavir 100 mg once daily for 10 days. cAdministered as combination oral contraceptive tablet: ethinyl estradiol 0.035 mg/norethindrone 0.5 mg. dSubjects were receiving fosamprenavir calcium/ritonavir for 10 days prior to the 4-day treatment period with both ketoconazole and fosamprenavir calcium/ritonavir. eData represent lopinavir concentrations. fCompared with lopinavir 400 mg/ritonavir 100 mg twice daily for weeks. gDose normalized to methadone 100 mg. The unbound concentration of the active moiety, R-methadone, was unchanged. hSubjects were receiving nevirapine for at least 12 weeks prior to trial. iComparison arm of rifabutin 300 mg once daily for weeks. AUC is AUC(0-48 h). Increase; Decrease; <-> No change or less than 10%); ND Interaction cannot be determined as minwas below the lower limit of quantitation. Table 13. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Amprenavir after Administration of Agenerase Coadministered Drug(s) and Dose(s)Dose ofAgenerasen% Change in Pharmacokinetic Parameters of Coadministered Drug (90% CI)C max AUCC min 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 days12 10( 24 to 7)<-><->Delavirdine600 mg twice daily for 10 days 600 mg twice daily for 10 days9 47 61 88 Ethinyl estradiol0.035 mg for cycle 1,200 mg twice daily for 28 days10<-><-> 32( to 79)Indinavir800 mg times day for weeks (fasted) 750 mg or 800 mg times day for weeks (fasted)9 22 38 27 Ketoconazole400 mg single dose 1,200 mg single dose12 19( to 33) 44( 31 to 59)NALamivudine150 mg single dose 600 mg single dose11<-><->NAMethadone44 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)6 12 15 14 Norethindrone1 mg for cycle 1,200 mg twice daily for 28 days10<-> 18( 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)7 21 19 48 Zidovudine300 mg single dose 600 mg single dose12 40( 14 to 71) 31( 19 to 45)NAaCompared with historical data. bMedian percent change; confidence interval not reported. Increase; Decrease; <->= No change (or less than 10%); NA C minnot calculated for single-dose trial; ND Interaction cannot be determined as minwas below the lower limit of quantitation. image1.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir calcium during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryLimited data are available for use of fosamprenavir calcium in pregnancy. fosamprenavir calcium 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 calcium/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 ConsiderationsVirologic Monitoring During Pregnancy and the Postpartum Period:Based on limited data on the use of fosamprenavir calcium during pregnancy, no dosage adjustments are required for pregnant patients who are already on stable twice-daily regimen of fosamprenavir calcium 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 fosamprenavir calcium 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 calcium (with or without ritonavir) are not available. DataHuman Data:fosamprenavir calcium 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 calcium /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 calcium /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 (AUC 0-24 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 (AUC 0-24 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. Patient Information available at https://www.sunpharma.com/usa/productsFOSAMPRENAVIR (foss-am-PREN-ah-ver) CALCIUM TABLETS, USPRx onlyWhat 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 tabletsFosamprenavir calcium tablets can cause serious side effects, including:Severe 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:hives or sores in your mouth, or your skin blisters and peelsswelling of your face, eyes, lips, tongue, or throattrouble swallowing or breathingFor more information about side effects, see What are the possible side effects of fosamprenavir calcium tabletsWhat are fosamprenavir calcium tabletsFosamprenavir calcium tablets are prescription medicines that are 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 calcium tablets are safe and effective in children younger than weeks of age.Do not take fosamprenavir calcium tablets if you:are allergicto 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. take any of the following medicines:alfuzosinrifampinergot including:dihydroergotamine mesylateergonovineergotamine tartratemethylergonovinecisaprideSt. Johns wort (Hypericum perforatum)lomitapidelovastatinsimvastatinpimozidedelavirdine mesylatesildenafil (Revatio), for treatment of pulmonary arterial hypertensiontriazolammidazolam, 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:flecainidepropafenonelurasidoneBefore taking fosamprenavir calcium tablets, tell your healthcare provider about all of your medical conditions, including if you:are allergic to medicines that contain sulfa.have or have had liver problems, including hepatitis or virus infection.have kidney problems.have high blood sugar (diabetes).have hemophilia.have high cholesterol.are 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. fosamprenavir 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. are breastfeeding or plan to breastfeed. Do not breastfeed if you take fosamprenavir calcium tablets. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if fosamprenavir calcium tablets can pass to your baby in your breast milk.Talk 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.You can ask your healthcare provider or pharmacist for list of medicines that interact with fosamprenavir calcium tablets.Do 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 tabletsTake fosamprenavir calcium tablets exactly as your healthcare provider tells you to take it.If 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.Stay under the care of healthcare provider during treatment with fosamprenavir calcium tablets.If your child is taking fosamprenavir calcium tablets, your childs healthcare provider will decide the right dose based on your childs weight.fosamprenavir calcium tablets tablets may be taken with or without food.Do 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.If you take too much 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:See What is the most important information should know about fosamprenavir calcium tabletsLiver 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. Diabetes 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. Changes in your immune system (Immune Reconstitution Syndrome)can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. Increase 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. Changes 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. Increased bleeding problems in some people with hemophilia.Some people with hemophilia have increased bleeding with protease inhibitors, including fosamprenavir calcium tablets. Kidney 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: pain in your sideblood in your urinepain when you urinateThe most common side effects of fosamprenavir calcium tablets in adults include:nauseadiarrheavomitingheadacherashThe most common side effects of fosamprenavir calcium tablets in children includevomiting 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 tabletsStore fosamprenavir calcium tablets at room temperature between 68 to 77 (20 to 25 C).Keep the bottle of fosamprenavir calcium tablets tightly closed. Protect from moisture.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 it was not prescribed. Do not give fosamprenavir calcium tablets to other people, even if they have the same symptoms you have. It 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 calcium Inactive ingredients:colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and povidone. The tablet coating contains the inactive ingredients ethylcellulose, ferric oxide red, hypromellose, talc, and titanium dioxide. The imprinting ink contains the inactive ingredients ferric oxide black, propylene glycol, and shellac. This Patient Information has been approved by the U.S. Food and Drug Administration.All trademarks are the property of their respective owners.Manufactured by:Ohm Laboratories Inc.New Brunswick, NJ 08901Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512June 2024 FDA-06. Severe skin reactions.fosamprenavir calcium tablets may cause severe or life-threatening skin reactions or rash. hives or sores in your mouth, or your skin blisters and peels. swelling of your face, eyes, lips, tongue, or throat. trouble swallowing or breathing. are allergicto 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. take any of the following medicines:. alfuzosin. rifampin. ergot including:. dihydroergotamine mesylate. ergonovine. ergotamine tartrate. methylergonovine. cisapride. St. Johns wort (Hypericum perforatum). lomitapide. lovastatin. simvastatin. pimozide. delavirdine mesylate. sildenafil (Revatio), for treatment of pulmonary arterial hypertension. triazolam. midazolam, when taken by mouth. flecainide. propafenone. lurasidone. are allergic to medicines that contain sulfa.. have or have had liver problems, including hepatitis or virus infection.. have kidney problems.. have high blood sugar (diabetes).. have hemophilia.. have high cholesterol.. are 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. fosamprenavir 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. fosamprenavir 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.. are breastfeeding or plan to breastfeed. Do not breastfeed if you take fosamprenavir calcium tablets. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.It is not known if fosamprenavir calcium tablets can pass to your baby in your breast milk.Talk with your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. It is not known if fosamprenavir calcium tablets can pass to your baby in your breast milk.. Talk with your healthcare provider about the best way to feed your baby.. You can ask your healthcare provider or pharmacist for list of medicines that interact with fosamprenavir calcium tablets.. Do 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. Take fosamprenavir calcium tablets exactly as your healthcare provider tells you to take it.. If 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.. Stay under the care of healthcare provider during treatment with fosamprenavir calcium tablets.. If your child is taking fosamprenavir calcium tablets, your childs healthcare provider will decide the right dose based on your childs weight.. fosamprenavir calcium tablets tablets may be taken with or without food.. Do 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.. If you take too much fosamprenavir calcium tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about fosamprenavir calcium tablets. Liver 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. Diabetes 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. Changes in your immune system (Immune Reconstitution Syndrome)can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. Increase 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. Changes 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. Increased bleeding problems in some people with hemophilia.Some people with hemophilia have increased bleeding with protease inhibitors, including fosamprenavir calcium tablets. Kidney 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: pain in your sideblood in your urinepain when you urinate. pain in your side. blood in your urine. pain when you urinate. nausea. diarrhea. vomiting. headache. rash. Store fosamprenavir calcium tablets at room temperature between 68 to 77 (20 to 25 C).. Keep the bottle of fosamprenavir calcium tablets tightly closed. Protect from moisture.

SPL UNCLASSIFIED SECTION.

2.1 General Dosing Information. Fosamprenavir calcium tablets may be taken with or without food.Adults should take fosamprenavir calcium oral suspension without food. Pediatric patients should take fosamprenavir calcium oral suspension with food [see Clinical Pharmacology (12.3)]. If emesis occurs within 30 minutes after dosing, re-dosing of fosamprenavir calcium oral suspension should occur. Higher-than-approved dose combinations of fosamprenavir calcium tablets plus ritonavir are not recommended due to an increased risk of transaminase elevations [see Overdosage (10)]. When fosamprenavir calcium tablets are used in combination with ritonavir, prescribers should consult the full prescribing information for ritonavir.

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 RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir calcium during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryLimited data are available for use of fosamprenavir calcium in pregnancy. fosamprenavir calcium 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 calcium/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 ConsiderationsVirologic Monitoring During Pregnancy and the Postpartum Period:Based on limited data on the use of fosamprenavir calcium during pregnancy, no dosage adjustments are required for pregnant patients who are already on stable twice-daily regimen of fosamprenavir calcium 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 fosamprenavir calcium 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 calcium (with or without ritonavir) are not available. DataHuman Data:fosamprenavir calcium 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 calcium /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 calcium /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 (AUC 0-24 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 (AUC 0-24 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 SummaryThe 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 calcium. DataAmprenavir 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. ContraceptionUse of fosamprenavir calcium 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 calcium 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 calcium is not recommended in protease inhibitor-experienced pediatric patients younger than months. The pharmacokinetics, safety, tolerability, and efficacy of fosamprenavir calcium 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 calcium 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 calcium 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 calcium to patients with hepatic impairment because amprenavir concentrations may be increased [see Clinical Pharmacology (12.3)]. Patients with impaired hepatic function receiving fosamprenavir calcium with or without concurrent ritonavir require dose reduction [see Dosage and Administration (2.4)]. There are no data to support dosing recommendations for pediatric subjects with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. The concomitant use of fosamprenavir calcium 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)Fosamprenavir calcium should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) Fosamprenavir calcium should be used with caution in patients with known sulfonamide allergy. (5.3) Use of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis or are at increased risk of transaminase elevations. (5.4)Patients receiving fosamprenavir calcium 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.Acute hemolytic anemia has been reported with amprenavir. (5.9)Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.10)Nephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. (5.11). The concomitant use of fosamprenavir calcium 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). Fosamprenavir calcium should be discontinued for severe skin reactions, including Stevens-Johnson syndrome. (5.2) Fosamprenavir calcium should be used with caution in patients with known sulfonamide allergy. (5.3) Use of higher-than-approved doses may lead to transaminase elevations. Patients with hepatitis or are at increased risk of transaminase elevations. (5.4). Patients receiving fosamprenavir calcium 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.. Acute hemolytic anemia has been reported with amprenavir. (5.9). Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.10). Nephrolithiasis: Cases of nephrolithiasis have been reported with fosamprenavir. (5.11). 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of fosamprenavir calcium/ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving fosamprenavir calcium/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 calcium/ritonavir, respectively. These interactions may lead to:clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.clinically significant adverse reactions from greater exposures of fosamprenavir calcium/ritonavir.loss of therapeutic effect of fosamprenavir calcium/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 calcium/ritonavir; review concomitant medications during therapy with fosamprenavir calcium/ritonavir, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4), Drug Interactions (7)]. clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.. clinically significant adverse reactions from greater exposures of fosamprenavir calcium/ritonavir.. loss of therapeutic effect of fosamprenavir calcium/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 calcium in clinical trials. Treatment with fosamprenavir calcium 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 calcium 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 calcium 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 calcium 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 calcium 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 calcium 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 calcium. 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 aviuminfection, cytomegalovirus, Pneumocystis jiroveciipneumonia [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 calcium. 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 calcium 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 calcium 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 calcium. 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 calcium will have on the activity of subsequently administered protease inhibitors. Fosamprenavir calcium has been studied in patients who have experienced treatment failure with protease inhibitors [see Clinical Studies (14.2)].