Atazanavir (Page 10 of 12)

14.2 Adult Patients with Prior Antiretroviral Therapy

Study AI424-045: Atazanavir once daily with ritonavir once daily compared to atazanavir once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. Study AI424-045 (NCT00035932): was a randomized, multicenter trial comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to atazanavir (400 mg once daily) with saquinavir soft gelatin capsules (1,200 mg once daily), and to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) subjects who experienced virologic failure on highly active antiretroviral therapy regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1,543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).

Treatment outcomes through Week 48 for the atazanavir with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that atazanavir with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification [see Microbiology, Tables 24 and 25 (12.4)].

Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Subjects with Prior Antiretroviral Experience)

Outcome

Atazanavir 300 mg with ritonavir 100 mg once daily and tenofovir DF and 1 NRTI

(n=119)

Lopinavir/ritonavir (400/100 mg) twice

daily and tenofovir DF and 1 NRTI

(n=118)

Differencea (atazanavir -lopinavir/ritonavir)b (CI)

HIV-1 RNA Change from Baseline (log10 copies/mL)c

−1.58

−1.70

+0.12c

(−0.17, 0.41)

CD4+ Change from Baseline (cells/mm3)e

116

123

−7

(−67, 52)

Percent of Subjects Respondinge

HIV-1 RNA < 400 copies/mLc

55%

57%

−2.2%

(−14.8%, 10.5%)

HIV-1 RNA < 50 copies/mLc

38%

45%

−7.1%

(−19.6%, 5.4%)

a Time-averaged difference through Week 48 for HIV-1 RNA; Week 48 difference in HIV-1 RNA percentages and CD4+ mean changes, atazanavir with ritonavir vs. lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV-1 RNA; 95% confidence interval otherwise.

b Administered as a fixed-dose product.

c Roche Amplicor® HIV-1 Monitor Assay, test version 1.5.

d Protocol-defined primary efficacy outcome measure.

e Based on subjects with baseline and Week 48 CD4+ cell count measurements (atazanavir with ritonavir, n=85; lopinavir/ritonavir, n=93).

f Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL (< 50 copies/mL) through Week 48.

No subjects in the atazanavir with ritonavir treatment arm and three subjects in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for atazanavir 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of subjects in this treatment arm with plasma HIV-1 RNA < 400 (< 50) copies/mL was 38% (26%). In this study, co-administration of atazanavir and saquinavir did not provide adequate efficacy [see Drug Interactions (7)].

Study AI424-045 also compared changes from baseline in lipid values [see Adverse Reactions (6.1)].

Study AI424-043 (NCT00028301): Study AI424-043 was a randomized, open-label, multicenter trial comparing atazanavir (400 mg once daily) to lopinavir/ritonavir (400 mg/100 mg twice daily as fixed-dose product), each in combination with two NRTIs, in 300 subjects who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of subjects with plasma HIV-1 RNA < 400 (< 50) copies/mL was 49% (35%) for subjects randomized to atazanavir (n=144) and 69% (53%) for subjects randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the atazanavir treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, atazanavir without ritonavir was inferior to lopinavir/ritonavir in PI-experienced subjects with prior virologic failure and is not recommended for such patients.

14.3 Pediatric Patients

Pediatric Trial with Atazanavir Capsules

Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of atazanavir capsules was based on data from this open-label, multicenter clinical trial which included subjects from 6 years to 21 years of age. In this study, 105 subjects (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily atazanavir capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) subjects (6 to less than 18 years of age) treated with the atazanavir capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA < 400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA < 50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive subjects and 220 cells/mm3 in antiretroviral-experienced subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING

Atazanavir Capsules, 100 mg are supplied as size ‘2’ hard gelatin capsules having imprinted ‘Amneal 100 mg’ on blue opaque cap with white ink and ‘1135’ on white opaque body with blue ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60: NDC 69238-1135-6

Atazanavir Capsules, 150 mg are supplied as size ‘1’ hard gelatin capsules having imprinted ‘Amneal 150 mg’ on blue opaque cap with white ink and ‘1136’ on powder blue opaque body with blue ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60: NDC 69238-1136-6

Atazanavir Capsules, 200 mg are supplied as size ‘0’ hard gelatin capsules having imprinted ‘Amneal 200 mg’ on blue opaque cap and ‘1137’on blue opaque body with white ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60: NDC 69238-1137-6

Atazanavir Capsules, 300 mg are supplied as size ‘00’ hard gelatin capsules having imprinted ‘Amneal 300 mg’ on red opaque cap and ‘1138’ on blue opaque body with white ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 30: NDC 69238-1138-3

Keep capsules in a tightly closed container.

Store atazanavir capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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