Fosamprenavir Calcium 700 mg Tablet, Coated, 60-count — NDC 63304-583-60 (Billing 63304-0583-60)

12 CLINICAL PHARMACOLOGY

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

12.3Pharmacokinetics 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 2 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 Adults Regimen C max (mcg/mL) T max (hours) a AUC 24 (mcg•h/mL) C tau b (mcg/mL) Fosamprenavir calcium 1,400 mg Twice Daily(n = 22) c 4.82 (4.06 to 5.72) 1.3 (0.8to 4) 33 d (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) e 7.24 (6.32 to 8.28) 2.1 (0.8t o 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) e 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) e 6.08 (5.38 to 6.86) 1.5 (0.75 to 5) 79.2 d (69 to 90.6) 2.12 (1.77 to 2.54) a Data shown are median (range). b C tau is the concentration at the end of the dose interval. c HIV-infected adults. d AUC 24 was calculated from AUC 12 summary data x 2. e Healthy 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 50 Values against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) Absorption After administration of a single dose of fosamprenavir calcium to HIV-1-infected subjects, the time to peak amprenavir concentration (T max ) occurred between 1.5 and 4 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 a 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 C max of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet. Amprenavir is both a substrate for and inducer of P-glycoprotein.

Effects of Food on Oral Absorption Administration of a 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 C max , T max , or AUC 0-∞ [see Dosage and Administration (2)] . Administration of a 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 a 46% reduction in C max , a 0.72-hour delay in T max , and a 28% reduction in amprenavir AUC 0-∞.

Distribution In 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 1 to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epit… [Excerpted — this section continues on DailyMed.]

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

12.3Pharmacokinetics 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 2 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 Adults Regimen C max (mcg/mL) T max (hours) a AUC 24 (mcg•h/mL) C tau b (mcg/mL) Fosamprenavir calcium 1,400 mg Twice Daily(n = 22) c 4.82 (4.06 to 5.72) 1.3 (0.8to 4) 33 d (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) e 7.24 (6.32 to 8.28) 2.1 (0.8t o 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) e 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) e 6.08 (5.38 to 6.86) 1.5 (0.75 to 5) 79.2 d (69 to 90.6) 2.12 (1.77 to 2.54) a Data shown are median (range). b C tau is the concentration at the end of the dose interval. c HIV-infected adults. d AUC 24 was calculated from AUC 12 summary data x 2. e Healthy 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 50 Values against HIV from Protease Inhibitor-Naive Subjects (in the Absence of Human Serum) Absorption After administration of a single dose of fosamprenavir calcium to HIV-1-infected subjects, the time to peak amprenavir concentration (T max ) occurred between 1.5 and 4 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 a 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 C max of amprenavir after administration of the suspension formulation was 14.5% higher compared with the tablet. Amprenavir is both a substrate for and inducer of P-glycoprotein.

Effects of Food on Oral Absorption Administration of a 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 C max , T max , or AUC 0-∞ [see Dosage and Administration (2)] . Administration of a 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 a 46% reduction in C max , a 0.72-hour delay in T max , and a 28% reduction in amprenavir AUC 0-∞.

Distribution In 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 1 to 10 mcg per mL, with decreased binding at higher concentrations. The partitioning of amprenavir into erythrocytes is low, but increases as amprenavir concentrations increase, reflecting the higher amount of unbound drug at higher concentrations.

Metabolism After oral administration, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. This occurs in the gut epithelium during absorption. Amprenavir is metabolized in the liver by the CYP3A4 enzyme system.

The 2 major metabolites result… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Therapy-Naive Adult Trials APV30001 A 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 C (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: 2 to 1,136 cells per mm 3 ; 18% of subjects had a CD4+ cell count of less than 50 cells per mm 3 and 30% were in the range of 50 to less than 200 cells per mm 3 ). Baseline median HIV-1 RNA was 4.83 log 10 copies per mL (range: 1.69 to 7.41 log 10 copies per mL; 45% of subjects had greater than 100,000 copies per mL). The outcomes of randomized treatment are provided in Table 15.

Table 15. Outcomes of Randomized Treatment through Week 48 (APV30001) Outcome (Rebound or discontinuation = failure) Fosamprenavir Calcium 1,400 mg Twice Daily Nelfinavir 1,250 mg Twice Daily (n = 166) (n = 83) Responder a 66% (57%) 52% (42%) Virologic failure 19% 32% Rebound 16% 19% Never suppressed through Week 48 3% 13% Clinical progression 1% 1% Death 0% 1% Discontinued due to adverse reactions 4% 2% Discontinued due to other reasons b 10% 10% a Subjects 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). b Includes 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 Calcium 1,400 mg Twice Daily Nelfinavir 1,250 mg Twice Daily < 400 copies/mL n < 400 copies/mL n ≤ 100,000 65% 93 65% 46 > 100,000 67% 73 36% 37 Through 48 weeks of therapy, the median increases from baseline in CD4+ cell counts were 201 cells per mm 3 in the group receiving fosamprenavir calcium and 216 cells per mm 3 in the nelfinavir group.

APV30002 A 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: 1 to 1,055 cells per mm 3 ; 20% of subjects had a CD4+ cell count of less than 50 cells per mm 3 and 35% were in the range of 50 to less than 200 cells per mm 3 ). Baseline median HIV-1 RNA was 4.81 log 10 copies per mL (range: 2.65 to 7.29 log 10 copies per mL; 43% of subjects had greater than 100,000 copies per mL). The outcomes of randomized treatment are provided in Table 17.

Table 17. Outcomes of Randomized Treatment through Week 48 (APV30002) Outcome (Rebound or discontinuation = failure) Fosamprenavir Calcium 1,400 mg/Ritonavir 200 mg Once Daily Nelfinavir 1,250 mg Twice Daily (n = 322) (n = 327) Responder a 69% (58%) 68% (55%) Virologic failure 6% 16% Rebound 5% 8% Never suppressed through Week 48 1% 8% Death 1% 0% Discontinued due to adverse reactions 9% 6% Discontinued due to other reasons b 15% 10% a Subjects 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). b Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, and othe… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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 a battery of in vitro and in vivo assays. 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 4 weeks before mating) and female rats (treated for 2 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 3 (males) to 4 (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.