CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Atazanavir is an HIV-1 antiretroviral drug [see Microbiology 12.4)]. 12.2 Pharmacodynamics. Cardiac Electrophysiology Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (+-SD) maximum change in PR interval from the predose value was 24 (+-15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (+-11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions 5.1)]. Electrocardiographic effects of atazanavir were determined in clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration- dependent effect of atazanavir on the QTc interval (using Fridericias correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had QTc interval >500 msec [see Warnings and Precautions 5.1)]. 12.3 Pharmacokinetics. The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17). Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or Subjects with HIV-1 Infection in the Fed State 400 mg once daily 300 mg with ritonavir 100 mg once daily HealthySubjects Subjects with HIV-1 Infection Healthy Subjects Subjects with HIV-1 Infection Parameter (n=14) (n=13) (n=28) (n=10) max (ng/mL) Geometric mean 5199 (26) 2298 (71) 6129 (31) 4422 (58) (CV%) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) max (h) Median 2.5 2.0 2.7 3.0 AUC (ngoh/mL) Geometric mean 28132 (28) 14874 (91) 57039 (37) 46073 (66) (CV%) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2) 8.6 (2.3) min (ng/mL) Geometric mean 159 (88) 120 (109) 1227 (53) 636 (97) (CV%) Mean (SD) 218 (191) 273 (298) 1441 (757) 862 (838) n=26. n=12. Figure displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200-mg capsules) with light meal and after atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with light meal in adult subjects with HIV-1 infection. Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Subjects with HIV-1 Infection Absorption Atazanavir is rapidly absorbed with T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and max values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days and 8, with an accumulation of approximately 2.3 fold. Food Effect Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of single 400 mg dose of atazanavir with light meal (357 kcal, 8.2 fat, 10.6 protein) resulted in 70% increase in AUC and 57% increase in max relative to the fasting state. Administration of single 400 mg dose of atazanavir with high-fat meal (721 kcal, 37.3 fat, 29.4 protein) resulted in mean increase in AUC of 35% with no change in max relative to the fasting state. Administration of atazanavir with either light meal or high-fat meal decreased the coefficient of variation of AUC and max by approximately one-half compared to the fasting state. Coadministration of single 300 mg dose of atazanavir and 100 mg dose of ritonavir with light meal (336 kcal, 5.1 fat, 9.3 protein) resulted in 33% increase in the AUC and 40% increase in both the max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with high-fat meal (951 kcal, 54.7 fat, 35.9 protein) did not affect the AUC of atazanavir relative to fasting conditions and the max was within 11% of fasting values. The 24-hour concentration following high-fat meal was increased by approximately 33% due to delayed absorption; the median max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either light or high-fat meal decreased the coefficient of variation of AUC and max by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to similar extent (89% and 86%, respectively). In multiple-dose study in subjects with HIV-1 infection dosed with atazanavir 400 mg once daily with light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately hours at steady state following dose of 400 mg daily with light meal. Specific Populations Renal Impairment In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir max was 9% lower, AUC was 19% higher, and min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for max, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis see Dosage and Administration (2.7)]. Hepatic Impairment Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh and Child-Pugh subjects) after single 400 mg dose. The mean AUC(0 to was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)]. Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric subjects taking the capsule formulation were predicted by population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Subjects with HIV-1 Infection Body Weight(range in kg) atazanavir with ritonavir Dose (mg) max ng/mL Geometric Mean (CV%) AUC ngoh/mL Geometric Mean (CV%)C min ng/mL Geometric Mean (CV%) 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) >=35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 infection receiving atazanavir capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 Infection in the Fed StateAtazanavir 300 mg with ritonavir 100 mgPharmacokinetic Parameter2nd Trimester(n=5 a) 3rd Trimester(n=20)Postpartum (n=34)C max ng/mL 3078.85 3291.46 5721.21 Geometric mean (CV%) (50) (48) (31) AUC ngoh/mL 27657.1 34251.5 61990.4 Geometric mean (CV%) (43) (43) (32) min ng/mL 538.70 668.48 1462.59 Geometric mean (CV%) (46) (50) (45) Available data during the 2nd trimester are limited. Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4 to 12 weeks) than those observed historically in, non-pregnant patients with HIV-1 Infection. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1 infection. C min is concentration 24 hours post-dose. Drug Interaction Data Atazanavir is metabolism-dependent CYP3A inhibitor, with K inact value of 0.05 to 0.06 min -1 and i value of 0.84 to 1.0 uM. Atazanavir is also direct inhibitor for UGT1A1 (K i=1.9 uM) and CYP2C8 (K i=2.1 uM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, max, and min are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs Coadministered DrugCoadministered DrugDose/ScheduleAtazanavir Dose/ScheduleRatio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/withoutCoadministered Drug; No Effect 1.00 CmaxAUCCmin atenolol 50 mg QD, 7-11 (n=19) and 19-23 400 mg QD, 1-11 (n=19) 1.00 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) clarithromycin 500 mg BID, 7-10 (n=29) and 18-21 400 mg QD, 1-10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T) ddI: 200 mg dose, d4T: 40 mg dose (n=31) 400 mg dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg dose, d4T: 40 mg dose (n=32) 400 mg dose h after ddI d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, 7-20 (n=27) 400 mg QD, 1-20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, 7-20 (n=13) 400 mg QD, 1-6 (n=23) then 300 mg with ritonavir 100 mg QD, h before efavirenz, 7-20 (n=13) 1.14 (0.83, 1.58) 1.39 (1.02, 1.88) 1.48 (1.24, 1.76) 600 mg QD, 11-24 (pm) (n=14) 300 mg QD with ritonavir 100 mg QD, 1-10 (pm) (n=22), then 400 mg QD with ritonavir 100 mg QD, 11-24 (pm), (simultaneously with efavirenz) (n=14) 1.1 (1.08, 1.27) 1.00 (0.91, 1.10) 0.58 (0.49, 0.69) famotidine 40 mg BID, 7-12 (n=15) 400 mg QD, 1-6 (n=45), 7-12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, 7-12 (n=14) 400 mg QD (pm), 1-6 (n=14), 7-12 (10 after, 12 before famotidine) (n=14) 1.08 (0.82, 1.41) 0.95 (0.74, 1.21) 0.79 (0.60, 1.04) 40 mg BID, 11-20 (n=14)c 300 mg QD with ritonavir 100 mg QD, 1-10 (n=46), 11-20d (simultaneous administration) (n=14) 0.86 (0.79, 0.94) 0.82 (0.75, 0.89) 0.72 (0.64, 0.81) 20 mg BID, 11-17 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 11-17 (am) (simultaneous administration with am famotidine) (n=18) d,e 0.91 (0.84, 0.99) 0.90 (0.82, 0.98) 0.81 (0.69, 0.94) 40 mg QD (pm), 18-24 (n=20) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 18-24 (am) (12 after pm famotidine) (n=20)e 0.89 (0.81, 0.97) 0.88 (0.80, 0.96) 0.77 (0.63, 0.93) 40 mg BID, 18-24 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 18-24 (am) (10 after pm famotidine and h before am famotidine) (n=18)e 0.74 (0.66, 0.84) 0.79 (0.70, 0.88) 0.72 (0.63, 0.83) 40 mg BID, 11-20 (n=15) 300 mg QD with ritonavir 100 mg QD and 1-10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD, 11-20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/ elbasvir grazoprevir 200 mg QD 1 35 (n 11) 300 mg QD with ritonavir 100 mg QD, 1- 35 (n 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD 1 35 (n 8) 300 mg QD with ritonavir 100 mg QD, 1 35 (n 8) 1.02 (0.96, 1.08) 1.07 (0.98, 1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, 7-13 (n=14) 400 mg QD, 1-13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapine f,g 200 mg BID, 1-23 (n=23) 300 mg QD with ritonavir 100 mg QD, 4-13, then 400 mg QD with ritonavir 100 mg QD, 14-23 (n=23)h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, 7-12 (n=16) 400 mg QD, 1-6 (n=48), 7-12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, 11-20 (n=15) 300 mg QD with ritonavir 100 mg QD, 1-20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, 17-23 (am) (n=13) 300 mg QD with ritonavir 100 mg QD, 7-16 (pm) (n=27), 17-23 (pm) (n=13) j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, 17-23 (am) (n=14) 300 mg QD with ritonavir 100 mg QD, 7-16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD, 17-23 (am) (n=14) l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin mg QD for days 300 mg QD for days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, 15-28 (n=7) 400 mg QD, 1-28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) rifampin 600 mg QD, 17-26 (n=16) 300 mg QD with ritonavir 100 mg QD, 7-16 (n=48), 17-26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavirn 100 mg QD, 11-20 (n=28) 300 mg QD, 1-20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DFo 300 mg QD, 9-16 (n=34) 400 mg QD, 2-16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, 15-42 (n=10) 300 mg with ritonavir 100 mg QD, 1-42 (n=10) 0.72p (0.50, 1.05) 0.75p (0.58, 0.97) 0.77p (0.54, 1.10) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, 2-3, 22-30; 400 mg BID, 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, 11-30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Subjects without functional CYP2C19 allele) 50 mg BID, 2-3, 22-30; 100 mg BID, 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, 11-30 (n=8) 0.81 (0.66, 1.00) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) Data provided are under fed conditions unless otherwise noted. All drugs were given under fasted conditions. Atazanavir 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean max that was similar and AUC and min values that were 1.79 -and 4.46-fold higher relative to atazanavir 400 mg once daily alone. Similar results were noted when famotidine 20 mg BID was administered hours after and 10 hours before atazanavir 300 mg and ritonavir 100 mg and tenofovir DF 300 mg. Coadministration of atazanavir with ritonavir and tenofovir DF was administered after light meal. Study was conducted in subjects with HIV-1 infection. Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg. Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Subjects were treated with nevirapine prior to study entry. Omeprazole 40 mg was administered on an empty stomach hours before atazanavir. Omeprazole 20 mg was administered 30 minutes prior to light meal in the morning and atazanavir 300 mg with ritonavir 100 mg in the evening after light meal, separated by 12 hours from omeprazole. Atazanavir 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and min (2.4-fold), with decrease in max (29%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1-6). Omeprazole 20 mg was given 30 minutes prior to light meal in the morning and atazanavir 400 mg with ritonavir 100 mg once daily after light meal, hour after omeprazole. Effects on atazanavir concentrations were similar when atazanavir 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. Atazanavir 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and min (3.3-fold), with decrease in Cmax (26%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1-6). Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir geometric mean values of max, AUC, and min by 18%, 103%, and 671%, respectively. Note that similar results were observed in studies where administration of tenofovir DF and atazanavir was separated by 12 hours. Ratio of atazanavir with ritonavir with tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnoteo). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: max 3190 ng/mL, AUC 34459 ngoh/mL, and Cmin 491 ng/mL. Study was conducted in subjects with HIV-1 infection. NA not available. Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Atazanavir Coadministered DrugCoadministered Drug Dose/ScheduleAtazanavir Dose/ScheduleRatio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without atazanavir; No Effect 1.00CmaxAUCCmin acetaminophen gm BID, 1-20 (n=10) 300 mg QD with ritonavir 100 mg QD, 11-20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, 7-11 (n=19) and 19-23 400 mg QD, 1-11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) clarithromycin 500 mg BID, 7-10 (n=21) and 18-21 400 mg QD, 1-10 (n=21) 1.50 (1.32, 1.71) OH- clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (entericcoated [EC] capsules)b 400 mg 1 (fasted), 8 (fed) (n=34) 400 mg QD, 2-8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg 1 (fasted), 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, 9-19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) diltiazem 180 mg QD, 7-11 (n=28) and 19-23 400 mg QD, 1-11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol norethindronec Ortho-Novum (R) 7/7/7 QD, 1-29 (n=19) 400 mg QD, 16-29 (n=19) ethinyl estradiol: 1.15 (0.99, 1.32) norethindrone: 1.67 (1.42, 1.96) ethinyl estradiol: 1.48 (1.31, 1.68) norethindrone: 2.10 (1.68, 2.62) ethinyl estradiol: 1.91 (1.57, 2.33) norethindrone: 3.62 (2.57, 5.09) ethinyl estradiol norgestimate Ortho Tri-Cyclen (R) QD, 1-28 (n=18), then Ortho Tri- Cyclen (R) LO QD, 29-42e (n=14) 300 mg QD with ritonavir 100 mg QD, 29-42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) 17-deacetyl norgestimate: 1.68 (1.51, 1.88) ethinyl estradiol: 0.81 (0.75, 0.87) 17-deacetyl norgestimate: 1.85 (1.67, 2.05) ethinyl estradiol: 0.63 (0.55, 0.71) 17-deacetyl norgestimate :f 2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) >=4.06g(3.15, 5.23) >=6.53g(5.24, 8.14) >=14.3 (9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) >=1.29g (1.15, 1.45) >=1.64g (1.48, 1.82) >=2.29 (1.95, 2.68) grazoprevir/ elbasvir grazoprevir 200 mg QD 1 35 (n=12) 300 mg QD with ritonavir 100 mg QD 1 35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD 1 35 (n=10) 300 mg QD with ritonavir 100 mg QD 1 35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, 1-15 (n=16) 400 mg QD, 2-15 (n=16) (R)-methadone 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadone 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadone 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapine i,j 200 mg BID, 1-23 (n=23) 300 mg QD with ritonavir 100 mg QD, 4-13, then 400 mg QDwith ritonavir 100 mg QD, 14-23 (n=23) 1.17 (1.09, 1.25) 1.21 (1.11, 1.32) 1.25 (1.17, 1.34) 1.26 (1.17, 1.36) 1.32 (1.22, 1.43) 1.35 (1.25, 1.47) omeprazolek 40 mg single dose, 7 and 20 (n=16) 400 mg QD, 1-12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, 1-10 then 150 mg QD, 11-20 (n=3) 600 mg QD, d 11-20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl- rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl- rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl- rifabutin: 75.6 (30.1, 190.0) 150 mg twice weekly, 1-15 (n=7) 300 mg QDwith ritonavir 100 mg QD, 1-17 (n=7) 2.49m (2.03, 3.06) 25-O-desacetyl- rifabutin: 7.77 (6.13, 9.83) 1.48m (1.19, 1.84) 25-O-desacetyl- rifabutin: 10.90 (8.14, 14.61) 1.40m (1.05, 1.87) 25-O-desacetyl- rifabutin: 11.45 (8.15, 16.10) pitavastatin mg QD for days 300 mg QD for days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazonen mg single dose, 1, 7, 17 (n=14) 400 mg QD, 2-7, then 300 mg QDwith ritonavir 100 mg QD, 8-17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QDwith ritonavir 100 mg QD for days 7-foldo 3-foldo NA saquinavir p(soft gelatin capsules) 1200 mg QD, 1-13 (n=7) 400 mg QD, 7-13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mgwith 100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mgwith 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DFq 300 mg QD, 9-16 (n=33) and 24-30 (n=33) 400 mg QD, d2-16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 300 mg QD, 1-7 (pm) (n=14) 25-34 (pm) (n=12) 300 mg QDwith ritonavir 100 mg QD, 25-34 (am) (n=12)r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, 2-3, 22-30; 400 mg BID, 1, 21 (n=20) 300 mgwith ritonavir 100 mg QD, 11-30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Subjects without functional CYP2C19 allele) 50 mg BID, 2-3, 22-30; 100 mg BID, 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, 11-30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, 1-12 (n=19) 400 mg QD, 7-12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1.00 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08) Data provided are under fed conditions unless otherwise noted. 400 mg ddI EC and atazanavir were administered together with food on Days and 19. Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. All subjects were on 28-day lead-in period; one full cycle of Ortho Tri-Cyclen (R). Ortho Tri-Cyclen (R) contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen (R) LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. 17-deacetyl norgestimate is the active component of norgestimate. Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported. (R)-methadone is the active isomer of methadone. Study was conducted subjects with HIV-1 infection. Subjects were treated with nevirapine prior to study entry. Omeprazole was used as metabolic probe for CYP2C19. Omeprazole was given hours after atazanavir on Day 7; and was given alone hours after light meal on Day 20. Not the recommended therapeutic dose of atazanavir. When compared to rifabutin 150 mg QD alone d1-10 (n=14). Total of rifabutin 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). Rosiglitazone used as probe substrate for CYP2C8. Mean ratio (with/without coadministered drug). indicates an increase in rosuvastatin exposure. The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. Note that similar results were observed in study where administration of tenofovir DF and atazanavir was separated by 12 hours. Administration of tenofovir DF and atazanavir was temporally separated by 12 hours. NA not available.. 12 before famotidine) atazanavircapsulecamberfigure. 12.4 Microbiology. Mechanism of Action Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Antiviral Activity in Cell Culture Atazanavir exhibits anti-HIV-1 activity with mean 50% effective concentration (EC 50) in the absence of human serum of to nM against variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. Atazanavir has activity against HIV-1 Group subtype viruses A, B, C, D, AE, AG, F, G, and isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Resistance In Cell Culture: HIV-1 isolates with decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies of Treatment-Naive Subjects: Comparison of Ritonavir-Boosted Atazanavir vs Unboosted Atazanavir: Study AI424-089 compared atazanavir 300 mg once daily with ritonavir 100 mg vs atazanavir 400 mg once daily when administered with lamivudine and extended- release stavudine in treatment-naive subjects with HIV-1 infection. summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23. Table 23: Summary of Virologic Failures at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted Atazanavir vs Unboosted Atazanavir: Randomized Patients Atazanavir 300 mgwith ritonavir 100 mg(n=95)Atazanavir 400 mg (n=105) Virologic Failure (350 copies/mL) at Week 96 15 (16%) 34 (32%) Virologic Failure with Genotypes and Phenotpyes Data 17 Virologic Failure Isolates with atazanavir resistance at Week 96 0/5 (0%) 4/17 (24%) Virologic Failure Isolates with I50L Emergence at Week 96 0/5 (0%) 2/17 (12%) Virologic Failure Isolates with Lamivudine Resistance at Week 96 2/5 (40%) 11/17 (65%) a Virologic failure includes subjects who were never suppressed through Week 96 and on study at Week 96, had virologic rebound or discontinued due to insufficient viral load response. Percentage of Virologic Failure Isolates with genotypic and phenotypic data. cMixture of I50I/L emerged in other ATV 400 mg-treated subjects. Neither isolate was phenotypically resistant to atazanavir. Clinical Studies of Treatment-Naive Subjects Receiving Atazanavir 300 mg with Ritonavir 100 mg: In Phase Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from subjects who experienced virologic failure (HIV-1 RNA 400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had 56-fold decrease in atazanavir susceptibility emerge on therapy with the development of PI resistance- associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the lopinavir/ritonavir arm, one of the virologic failure patient isolates had 69-fold decrease in lopinavir susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six lopinavir with ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance. Clinical Studies of Treatment-Naive Subjects Receiving Atazanavir 400 mg without Ritonavir: Atazanavir-resistant clinical isolates from treatment-naive subjects who experienced virologic failure on atazanavir 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive subjects, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs. Clinical Studies of Treatment-Experienced Subjects: In studies of treatment-experienced subjects treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from subjects who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of subjects who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of subject isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the subject at baseline, atazanavir resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced subjects experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment but their presence did not correlate with the level of atazanavir resistance. Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one subject among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold-change of 3.5, with ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one subject each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two subjects who failed treatment with atazanavir with ritonavir. Viruses from nine subjects in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1). Cross-Resistance Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced subjects showed that isolates cross- resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or change at V82 were resistant to atazanavir, and 38% of isolates containing D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced subjects, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs. Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced subjects receiving atazanavir with ritonavir once daily or lopinavir/ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24. Overall, both the number and type of baseline PI substitutions affected response rates in treatment- experienced subjects. In the atazanavir with ritonavir group, subjects had lower response rates when or more baseline PI substitutions, including substitution at position 36, 71, 77, 82, or 90, were present compared to subjects with to PI substitutions, including one of these substitutions. Table 24: HIV-1 RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Subjects in Study AI424-045, As-Treated Analysis Virologic Response HIV RNA <400 copies/mL Number and Type of Baseline PIatazanavir with ritonavirlopinavir/ritonavir Substitutions (n=110)(n=113)3 or more primary PI substitutionsincluding d: D30N 75% (6/8) 50% (3/6) M36I/V 19% (3/16) 33% (6/18) M46I/L/T 24% (4/17) 23% (5/22) I54V/L/T/M/A 31% (5/16) 31% (5/16) A71V/T/I/G 34% (10/29) 39% (12/31) G73S/A/C/T 14% (1/7) 38% (3/8) V77I 47% (7/15) 44% (7/16) V82A/F/T/S/I 29% (6/21) 27% (7/26) I84V/A 11% (1/9) 33% (2/6) N88D 63% (5/8) 67% (4/6) L90M 10% (2/21) 44% (11/25) Number of baseline primary PI substitutionsAll patients, as-treated 58% (64/110) 59% (67/113) 0-2 PI substitutions 75% (50/67) 75% (50/67) 3-4 PI substitutions 41% (14/34) 43% (12/28) or more PI substitutions 0% (0/9) 28% (5/18) Primary substitutions include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. Results should be interpreted with caution because the subgroups were small. Administered as fixed-dose product. There were insufficient data (n<3) for PI substitutions V32I, I47V, G48V, I50V, and F53L. The response rates of antiretroviral-experienced subjects in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on select population with 62% of subjects receiving an NNRTI-based regimen before study entry compared to 35% receiving PI-based regimen. Additional data are needed to determine clinically relevant break points for atazanavir. Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Subjects in Study AI424-045, As-Treated Analysis Virologic Response HIV RNA<400 copies/mL Baseline Phenotype atazanavir with ritonavir (n=111)lopinavir/ritonavir (n=111)0-2 71% (55/78) 70% (56/80) >2-5 53% (8/15) 44% (4/9) >5-10 13% (1/8) 33% (3/9) >10 10% (1/10) 23% (3/13) Fold change susceptibility in cell culture relative to the wild-type reference. Results should be interpreted with caution because the subgroups were small. Administered as fixed-dose product.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling: cardiac conduction abnormalities see Warnings and Precautions (5.1)] rash see Warnings and Precautions (5.2)] hyperbilirubinemia see Warnings and Precautions (5.8)] chronic kidney disease see Warnings and Precautions (5.5)] nephrolithiasis and cholelithiasis see Warnings and Precautions (5.6)] Most common adverse reactions (>=2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adverse Reactions in Treatment-Naive Adult Subjects The safety profile of atazanavir in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 patients received atazanavir 300 mg with ritonavir 100 mg and 1089 patients received atazanavir 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in >2% of treatment- naive patients receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) are presented in Tables and 8, respectively. Table 7: Selected Adverse Reactions of Moderate or Severe Intensity Reported in >2% of Adult Treatment-Naive Subjects with HIV-1 Infection, Study AI424-138 96 weeks 96 weeks Atazanavir capsules 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine lopinavir/ritonavir 400 mg/ 100 mg (twice daily) and tenofovir DF/emtricitabine (n=441)(n=441)Digestive SystemNausea4%8%Jaundice/scleral icterus5 Diarrhea2%12%Skin and AppendagesRash3%2% None reported in this treatment arm.a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on the regimen containing atazanavir. Median time on therapy. Administered as fixed-dose As fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. Table 8: Selected Adverse Reactions of Moderate or Severe Intensity Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection, Studies AI424-034, AI424-007, and AI424-008 Study AI424-034Studies AI424-007, -00864 weeks 64 weeks 120 weeks c,d 73 weeks c,d Atazanavir capsules 400 mg (once daily) with lamivudine/Zidovudine (n=404)efavirenz600 mg (once daily) with lamivudine/zidovudine (n=401)Atazanavir capsules 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279)nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191)Body as WholeHeadache 6% 6% 1% 2% Digestive SystemNausea 14% 12% 6% 4% Jaundice/scleral icterus 7% 7% Vomiting 4% 7% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous SystemInsomnia 3% 3% <1% Dizziness 2% 7% <1% Peripheral neurologic symptoms <1% 1% 4% 3% Skin and AppendagesRash 7% 10% 5% 1% None reported in this treatment arm. Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on regimens containing atazanavir. Median time on therapy. Includes long-term follow-up. As fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Adverse Reactions in Treatment-Experienced Adult Subjects The safety profile of atazanavir in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in >2% of treatment- experienced patients receiving atazanavir with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions of Moderate or Severe Intensity Reported in >=2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045 48 weeks 48 weeks Atazanavir capsules with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI(n=119)lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and NRTI(n=118)Body as WholeFever2%Digestive SystemJaundice/scleral icterus9%Diarrhea3%11%Nausea3%2%Nervous SystemDepression2%<1%Musculoskeletal SystemMyalgia4% None reported in this treatment arm.a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on the regimen containing atazanavir. Median time on therapy. As fixed-dose product. Laboratory Abnormalities in Treatment-Naive Subjects The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy including atazanavir 300 mg with ritonavir 100 mg or atazanavir 400 mg (without ritonavir) with Grade to laboratory abnormalities are presented in Tables 10 and 11, respectively Table 10: Grade to Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,a Study AI424-138 96 weeks 96 weeks Atazanavir capsules 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine lopinavir/ritonavir400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabine VariableLimit (n=441)(n=437)Chemistry High SGOT/AST >=5.1 ULN 3% 1% SGPT/ALT >=5.1 ULN 3% 2% Total Bilirubin >=2.6 ULN 44% <1% Lipase >=2.1 ULN 2% 2% Creatine Kinase >=5.1 ULN 8% 7% Total Cholesterol >=240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm3 5% 2% Based on the regimen containing atazanavir. Median time on therapy. Administered as affixed-dose product As fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. ULN upper limit of normal. Table 11: Grade to Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,a Studies AI424-034, AI424-007, and AI424-008 Study AI424-034Studies AI424-007, -008 64 weeksb64 weeks 120 weeks b, 73 weeks bc Atazanavir capsules 400 mg once daily and lamivudine/Zidovudinee efavirenz600 mg once daily and lamivudine/zidovudinee Atazanavir capsules 400 mg once daily with stavudine and lamivudine or with stavudine and didanosinenelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosineVariableLimit (n=404)(n=401)(n=279)(n=191)Chemistry High SGOT/AST >=5.1 ULN 2% 2% 7% 5% SGPT/ALT >=5.1 ULN 4% 3% 9% 7% Total >=2.6 ULN 35% <1% 47% 3% Bilirubin Amylase >=2.1 ULN 14% 10% Lipase >=2.1 ULN <1% 1% 4% 5% Creatine >=5.1 xULN 6% 6% 11% 9% Kinase Total >=240 mg/dL 6% 24% 19% 48% Cholesterol Triglycerides >=751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 37% 9% 3% 7% None reported in this treatment arm. Based on regimen(s) containing atazanavir. Median time on therapy. Includes long-term follow-up. ULN upper limit of normal. As fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 Infection For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL- cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 Atazanavir capsules with ritonavir a,b lopinavir/ritonavir b,c BaselineWeek 48Week 96BaselineWeek 48Week 96 mg/dLmg/dLChange mg/dLChange mg/dLmg/dLChangedmg/dLChange (n=428e)(n=372e)(n=372e)(n=342e)(n=342e) (n=424 e) (n=335 e) (n=335 e) (n=291e)(n=291 e) LDL- Cholesterol 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL- Cholesterol 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides 126 145 +15% 140 +13% 129 194 +52% 184 +50% Atazanavir 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir with ritonavir arm. Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 or Week 96 values and is not simple difference of the baseline and Week 48 or Week 96 mean values, respectively. Number of patients with LDL-cholesterol measured. Fasting. Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 Atazanavir capsules a,b efavirenz b,c Baselinemg/dLWeek 48mg/dLWeek 96Change Baselinemg/dLWeek 48mg/dLWeek 96Change (n=383 e) (n=283 e) (n=272 e) (n=378 e) (n=264 e) (n=253 e) LDL- Cholesterol 98 98 +1% 98 114 +18% HDL- Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides 138 124 -9% 129 168 +23% Atazanavir 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the atazanavir arm.Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the atazanavir arm. Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. The change from baseline is the mean of within-subject changes from baseline for patients with both baseline and Week 48 values and is not simple difference of the baseline and Week 48 mean values. Number of subjects with LDL-cholesterol measured. Fasting. Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including atazanavir with ritonavir having Grade to laboratory abnormalities, are presented in Table 14. Table 14: Grade to Laboratory Abnormalities Reported in >=2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045 Variable Limit 48 weeks Atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks lopinavir/ritonavir400/100 mg (twice daily d) and tenofovir DF and NRTI (n=118) Chemistry High SGOT/AST >=5.1 ULN 3% 3% SGPT/ALT >=5.1 ULN 4% 3% Total Bilirubin >=2.6 ULN 49% <1% Lipase >=2.1 ULN 5% 6% Creatine Kinase >=5.1 ULN 8% 8% Total Cholesterol >=240 mg/dL 25% 26% Triglycerides >=751 mg/dL 8% 12% Glucose >=251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 32% 3% Neutrophils <750 cells/mm 37% 8% Based on regimen(s) containing atazanavir. Median time on therapy. ULN upper limit of normal. As fixed-dose product. Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with atazanavir with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 Atazanavir with ritonavir a,b lopinavir/ritonavir b,c Baseline mg/dLWeek 48 mg/dLWeek 48 Change Baseline mg/dLWeek 48 mg/dLWeek 48 Change (n=111 e) (n=75 e) (n=74 e) (n=108 e) (n=76 e) (n=73 e) LDL-Cholesterol 108 98 -10% 104 103 +1% HDL-Cholesterol 40 39 -7% 39 41 +2% Total Cholesterol 188 170 -8% 181 187 +6% Triglyceridesf 215 161 -4% 196 224 +30% Atazanavir 300 mg once daily with ritonavir and tenofovir DF, and NRTI. Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir with ritonavir arm. Lopinavir/ritonavir (400/100 mg), as fixed dose regimen, BID with tenofovir DF and NRTI. The change from baseline is the mean of within-subject changes from baseline for patients with both baseline and Week 48 values and is not simple difference of the baseline and Week 48 mean values. Number of patients with LDL-cholesterol measured. Fasting. Adverse Reactions in Pediatric Subjects with HIV-1 Infection: Atazanavir Capsules The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of atazanavir in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade to adverse events (>=5%, regardless of causality) reported in pediatric subjects were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of subjects. The most common Grade to laboratory abnormalities occurring in pediatric subjects taking the capsule formulation were elevation of total bilirubin (>=3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade to laboratory abnormalities occurred with frequency of less than 3%. Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis and/or Hepatitis Virus In Study AI424-138, 60 subjects administered atazanavir 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis and/or at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir. In Study AI424-045, 20 subjects administered atazanavir 300 mg with ritonavir 100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis and/or at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the subjects administered atazanavir with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir-treated. AST levels >5 times ULN developed in 10% (2/20) of the subjects administered atazanavir with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 subjects treated with atazanavir 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis and/or at study entry. ALT levels >5 times ULN developed in 15% of the subjects treated with atazanavir, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with atazanavir, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects see Warnings and Precautions 5.8) ]. 6.2 Postmarketing Experience. The following events have been identified during postmarketing use of atazanavir. 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. Body as Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation see Warnings and Precautions 5.1) Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis see Warnings and Precautions 5.6) ], cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia see Warnings and Precautions 5.9) Musculoskeletal System: arthralgia Renal System: nephrolithiasis see Warnings and Precautions 5.6) ], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease see Warnings and Precautions 5.5) Skin and Appendages: alopecia, maculopapular rash see Contraindications 4) and Warnings and Precautions 5.2) ], pruritus, angioedema.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adult Patients without Prior Antiretroviral Therapy. Study AI424-138: 96-week study comparing the antiviral efficacy and safety of either atazanavir or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive subjects with HIV-1infection. Study AI424-138 (NCT00272779) was 96-week, open-label, randomized, multicenter study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive subjects. Subjects had mean age of 36 years (range: 19 to 72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm (range: to 810 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26. Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138) Outcome Atazanavir300 mg with ritonavir 100 mg(once daily) andtenofovir DF/emtricitabine(once daily)a(n=441) 6 Weeks lopinavir/ritonavir b400 mg/100 mg (twice daily) withtenofovir DF/emtricitabine(once daily)a(n=437) 6 Weeks Responderc,d,e 75% 68% Virologic failure 17% 19% Rebound 8% 10% Never suppressed through Week 96 9% 9% Death 1% 1% Discontinued due to adverse event 3% 5% Discontinued for other reasons 4% 7% As fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. As fixed-dose product: 400 mg lopinavir/100 mg ritonavir (twice daily). Subjects achieved HIV-1 RNA <50 copies/mL at Week 96. Roche Amplicor(R), v1.5 ultra-sensitive assay. Pre-specified ITT analysis at Week 48 using as-randomized cohort: atazanavir with ritonavir 78% and lopinavir/ritonavir 76% (difference estimate: 1.7% [95% confidence interval: -3.8%, 7.1%]). Pre-specified ITT analysis at Week 96 using as-randomized cohort: atazanavir with ritonavir 74% and lopinavir/ritonavir 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]). Includes viral rebound and failure to achieve confirmed HIV-1 RNA <50 copies/mL through Week 96. Includes lost to follow-up, subjects withdrawal, noncompliance, protocol violation, and other reasons. Through 96 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV-1 RNA >100,000 copies/mL) was comparable for the atazanavir with ritonavir (165 of 223 subjects, 74%) and lopinavir/ritonavir (148 of 222 subjects, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the atazanavir with ritonavir arm and 273 cells/mm for the lopinavir/ritonavir arm. Study AI424-034: Atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was randomized, double-blind, multicenter trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine /zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive subjects. Subjects had mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm (range: 64 to 1424 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.8 log 10 copies/mL (range: 2.2 to 5.9 log 10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27. Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034) Outcome Atazanavir400 mg once daily and lamivudine/zidovudine (n=405)efavirenz 600 mg once daily and lamivudine/zidovudine (n=405) Responder 67% (32%) 62% (37%) Virologic failure 20% 21% Rebound 17% 16% Never suppressed through Week 48 3% 5% Death <1% Discontinued due to adverse event 5% 7% Discontinued for other reasons 8% 10% Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor(R) HIV-1 Monitor TM Assay, test version 1.0 or 1.5 as geographically appropriate. Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. Includes lost to follow-up, patients withdrawal, noncompliance, protocol violation, and other reasons. As fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Through 48 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV-1 RNA >=100,000 copies/mL) was comparable for the atazanavir and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the atazanavir arm and 160 cells/mm for the efavirenz arm. Study AI424-008: Atazanavir 400 mg once daily compared to atazanavir 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was 48-week, randomized, multicenter trial, blinded to dose of atazanavir, comparing atazanavir at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive subjects. Subjects had mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm (range: to 1003 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.7 log 10 copies/mL (range: 1.8 to 5.9 log 10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28. Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008) Outcome Atazanavir400 mg once daily with lamivudine and stavudine(n=181) nelfinavir1250 mg twice daily with lamivudine and stavudine(n=91) Responder 67% (32%) 59% (38%) Virologic failure 20% 27% Rebound 14% 14% Never suppressed through Week 48 10% 13% Death <1% Discontinued due to adverse event 1% 3% Discontinued for other reasonsc 7% 10% Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor (R) HIV-1 Monitor(TM) Assay, test version 1.0 or 1.5 as geographically appropriate. Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. Includes lost to follow-up, subjects withdrawal, noncompliance, protocol violation, and other reasons. Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm for the atazanavir 400 mg arm and 211 cells/mm for the nelfinavir arm. 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 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 (1200 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/mm (range: 14 to 1543 cells/mm 3) and the mean baseline plasma HIV-1 RNA level was 4.4 log 10 copies/mL (range: 2.6 to 5.88 log 10 copies/mL). Treatment outcomes through Week 48 for the atazanavir with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir/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 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 withritonavir 100 mg oncedaily and tenofovir DF and NRTI(n=119)lopinavir/ritonavir (400/100 mg) twice daily andtenofovir DF +1 NRTI(n=118)Difference (Atazanavir -lopinavir/ritonavir) (CI)HIV-1 RNA Change from Baseline (log 10 copies/mL) -1.58 -1.70+0.12 (-0.17, 0.41) CD4+ Change from Baseline (cells/mm 3) 116 123-7 (-67, 52) Percent of Patients Responding HIV-1 RNA <400 copies/mL 55% 57%-2.2% (-14.8%, 10.5%) HIV-1 RNA <50 copies/mL 38% 45%-7.1% (-19.6%, 5.4%) 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. Administered as fixed-dose product. Roche Amplicor (R)HIV-1 Monitor TMAssay, test version 1.5. Protocol-defined primary efficacy outcome measure. Based on subjects with baseline and Week 48 CD4+ cell count measurements (atazanavir with ritonavir, n=85; lopinavir/ritonavir, n=93). 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 new-onset CDC Category 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 log 10 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/mm 3. 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, coadministration 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 randomized, open-label, multicenter trial comparing atazanavir (400 mg once daily) to lopinavir/ritonavir (400/100 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 atazanvir (n=144) and 69% (53%) for subjects randomized to lopinavir/ritonavir (n=146). The mean change from baseline was -1.59 log 10 copies/mL in the atazanvir treatment arm and -2.02 log 10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, atazanvir without ritonavir was inferior to lopinavir/ritonavir in PI-experienced subjects with prior virologic failure and is not recommended for such patients. 14.3Pediatric Patients. Pediatric Trials with Atazanavir Capsules Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of atazanvir capsules was based on data from this open-label, multicenter clinical trial which included subjects from years to 21 years of age. In this study, 105 subjects (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily atazanvir 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 atazanvir 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/mm in antiretroviral-naive subjects and 220 cells/mm in antiretroviral-experienced subjects.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Coadministration of atazanavir can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. 4, 7, 12.3) 7.1 Potential for Atazanavir to Affect Other Drugs. Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 12.3)]. The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 7.2 Potential For Other Drugs To Affect Atazanavir. Atazanavir is CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir therapeutic effect. Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with atazanavir [see Dosage and Administration 2.3, 2.4, and 2.6)] . 7.3 Established and Other Potentially Significant Drug Interactions. Table 16 provides dosing recommendations in adults as result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactions (Information in the table applies to atazanavir with or without ritonavir, unless otherwise indicated) Concomitant Drug Class:Specific DrugsEffect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral AgentsNucleoside Reverse Transcriptase Inhibitors (NRTIs):didanosine buffered formulations enteric-coated (EC) capsules atazanavir didanosine Coadministration of atazanavir with didanosine buffered tablets resulted in marked decrease in atazanavir exposure. It is recommended that atazanavir be given (with food) h before or h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors:tenofovir disoproxil fumarate (DF) atazanavir tenofovir Tenofovir DF may decrease the AUC and minof atazanavir. When coadministered with tenofovir DF in adults, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as single daily dose with food). Atazanavir increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking atazanavir with ritonavir andtenofovir DF, see Dosage and Administration 2.6) Non-nucleoside ReverseTranscriptase Inhibitors(NNRTIs):efavirenz atazanavir Efavirenz decreases atazanavir exposure. In treatment-naive adult patients: If atazanavir is combined with efavirenz, atazanavir 400 mg (two 200 mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced adult patients: Coadministration of atazanavir with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure. nevirapine atazanavir nevirapine Coadministration of atazanavir with nevirapine is contraindicated. This is due to substantial decreases in atazanavir exposure, which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures [see Contraindications 4)]. Protease Inhibitors:saquinavir (soft gelatin capsules) saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In clinical study, saquinavir 1200 mg coadministered with atazanavir 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies 14.2)] indinavir Coadministration of atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications( 4)]. ritonavir -atazanavir If atazanavir is coadministered with ritonavir, it is recommended that atazanavir 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others -other protease inhibitor Although not studied, the coadministration of atazanavir with ritonavir and an additional protease inhibitor would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended. Hepatitis Antiviral Agentselbasvir/grazoprevir -grazoprevir Coadministration of atazanavir with grazoprevir is contraindicated. The resulting increase in grazoprevir plasma concentrations can lead to an increased risk of ALT elevations [see Contraindications 4)]. glecaprevir/pibrentasvir -glecaprevir -pibrentasvir Coadministration of atazanavir with glecaprevir/pibrentasvir is contraindicated. It may increase the risk of ALT elevations due to an increase in glecaprevir and pibrentasvir concentrations [see Contraindications 4)]. voxilaprevir/sofosbuvir/ velpatasvir -voxilaprevir Coadministration with atazanavir is not recommended. Other AgentsAlpha 1-Adrenoreceptor Antagonist:alfuzosin -alfuzosin Coadministration of atazanavir with alfuzosin is contraindicated. The resulting increase in alfuzosin plasma concentrations can lead to hypotension [see Contraindications 4)]. Antacids and buffered medicationsatazanavir Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with atazanavir. Atazanavir should be administered hours before or hour after these medications. Antiarrhythmics:amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine -amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of atazanavir with ritonavir and either quinidine or amiodarone is contraindicated. This is due to the potential for substantial increase in systemic exposure of either quinidine or amiodarone, which may result in serious or life-threatening reactions such as cardiac arrhythmias [(see Contraindications 4)]. Coadministration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir. Anticoagulants:warfarin -warfarin Coadministration with atazanavir has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting OralAnticoagulants:betrixaban, dabigatran, edoxaban betrixaban dabigatran edoxaban Concomitant use of atazanavir with ritonavir, strong CYP3A4/P-gp inhibitor, with either betrixaban, dabigatran, or edoxaban may result in increased exposure of the respective DOAC that could lead to an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban apixaban Atazanavir with ritonavir rivaroxaban Atazanavir rivaroxaban Atazanavir with ritonavir apixaban Atazanavir apixaban Coadministration of atazanavir with ritonavir and rivaroxaban is not recommended. Concomitant treatment with agents that are combined Pglycoprotein (P-gp) strong CYP3A4 inhibitors, such as ritonavir, increase exposure to rivaroxaban and may increase risk of bleeding. Coadministration of atazanavir, CYP3A4 inhibitor, and rivaroxaban may result in increased increase exposure to rivaroxaban and may increase risk of bleeding. Close monitoring is recommended when atazanavir is coadministered with rivaroxaban. Concomitant use of atazanavir with ritonavir, strong CYP3A4/P-gp inhibitor, with apixaban may result in increased exposure of apixaban, which could lead to an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. Concomitant use of atazanavir, CYP3A4 inhibitor, and apixaban may result in increased exposure of apixaban, which could lead to an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with atazanavir. Antidepressants:tricyclic antidepressants -tricyclic antidepressants Coadministration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir. trazodone -trazodone Concomitant use of trazodone and atazanavir with or without ritonavir may increase plasma concentrations of trazodone. Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with CYP3A4 inhibitor such as atazanavir, the combination should be used with caution and lower dose of trazodone should be considered. Antiepileptics:carbamazepine atazanavir -carbamazepine Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with atazanavir without ritonavir. Coadministration of carbamazepine and atazanavir without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with atazanavir with ritonavir have been titrated to stable dose of carbamazepine, dose reduction for carbamazepine may be necessary. phenytoin, phenobarbital atazanavir phenytoin phenobarbital Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with atazanavir without ritonavir. Coadministration of phenytoin or phenobarbital and atazanavir without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When atazanavir with ritonavir is coadministered with either phenytoin or phenobarbital, dose adjustment of phenytoin or phenobarbital may be required. lamotrigine lamotrigine Coadministration of lamotrigine and atazanavir withritonavir may decrease lamotrigine plasma concentrations, and may require dosage adjustment of lamotrigine. Coadministration of lamotrigine and atazanavir withoutritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with atazanavir without ritonavir. Antifungals:ketoconazole, itraconazole Atazanavir with ritonavir:ketoconazole -itraconazole Coadministration of ketoconazole has only been studied with atazanavir without ritonavir (negligible increase in atazanavir AUC and max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with atazanavir with ritonavir. Voriconazole Atazanavirwith ritonavir in subjects with functional CYP2C19 allele:voriconazole atazanavir Atazanavirwith ritonavir in subjects without functional CYP2C19 allele: -voriconazole atazanavir The use of voriconazole in patients receiving atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and atazanavir with ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout:colchicine -colchicine The coadministration of atazanavir colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with atazanavir: Treatment of gout flares: 0.6 mg (1 tablet) for dose, followed by 0.3 mg (half tablet) hour later. Not to be repeated before days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twicea day, the regimen should be adjusted to 0.3 mg once day. If the original regimen was 0.6 mg oncea 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). Antimycobacterials:rifampin atazanavir Coadministration of atazanavir with rifampin is contraindicated. Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance [see Contraindications 4)]. rifabutin -rifabutin rifabutin dose reduction of up to 75% (eg, 150 mg every other day or times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antineoplastics:irinotecan-irinotecan Coadministration of atazanavir with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications 4)]. Antipsychotics:pimozide -pimozide Coadministration of atazanavir with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications 4)] lurasidone quetiapine Atazanavir with ritonavir -lurasidone Atazanavir -lurasidone -quetiapine Atazanavir with ritonavirCoadministration of lurasidone with atazanavir with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications 4)]. Atazanavir without ritonavirIf coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. Initiation ofatazanavir with ritonavir in patients taking quetiapine:Consider alternative antiretroviral therapy to avoid increases in quetiapine 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 takingatazanavir with ritonavir:Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines:midazolam (oral) triazolam -midazolam -triazolam Coadministration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Atazanavir may cause large increases in the concentration of these benzodiazepines that can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications 4)]. parenterally administered midazolam -midazolam Concomitant use of parenteral midazolam with atazanavir may increase plasma concentrations of midazolam. Coadministration should be done in setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than single dose of midazolam is administered. Calcium channel blockers:diltiazem -diltiazem and desacetyl-diltiazem Caution is warranted. dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and atazanavir with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil -calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Endothelin receptorantagonists:bosentan atazanavir -bosentan Plasma concentrations of atazanavir may be decreased when bosentan is administered with atazanavir without ritonavir. Coadministration of bosentan and atazanavir without ritonavir is not recommended. Coadministration of bosentan in adult patients on atazanavir with ritonavir: For patients who have been receiving atazanavir with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Coadministration of atazanavir with ritonavir in adult patients on bosentan: Discontinue bosentan at least 36 hours before starting atazanavir with ritonavir. At least 10 days after starting atazanavir with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives:dihydroergotamine, ergotamine, ergonovine, methylergonovine -ergot derivatives Coadministration of atazanavir with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications 4)]. GI Motility Agents:cisapride -cisapride Coadministration of atazanavir with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications 4)]. Herbal Products:St. Johns wort (Hypericum perforatum) atazanavir Coadministration of products containing St. Johns wort with atazanavir is contraindicated. This may result in loss of therapeutic effect of atazanavir and the development of resistance [see Contraindications 4)]. Lipid-modifying agents HMG-CoA reductase inhibitors:lovastatin, simvastatin lovastatin simvastatin Coadministration of atazanavir with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)]. atorvastatin, rosuvastatin atorvastatin rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including atazanavir, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapidelomitapide Coadministration of atazanavir with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications 4)]. H2-Receptor antagonistsatazanavir Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily in adults, which may result in loss of therapeutic effect and development of resistance. In treatment-naive adult patients: Atazanavir 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, dose of the 2-receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to dose comparable to famotidine 40 mg twice daily can be used with atazanavir 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, atazanavir 400 mg once daily with food should be administered at least hours before and at least 10 hours after dose of the H2RA. No single dose of the H2RA should exceed dose comparable to famotidine 20 mg, and the total daily dose should not exceed dose comparable to famotidine 40 mg. The use of atazanavir without ritonavir in pregnant women is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to patient receiving atazanavir with ritonavir, the H2RA dose should not exceed dose comparable to famotidine 20 mg twice daily, and the atazanavir and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. .Atazanavir 300 mg with ritonavir 100 mgonce daily (all as single dose with food) if taken with an H2RA. .Atazanavir 400 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with both tenofovir DF and an H2RA. .Atazanavir 400 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester.Atazanavir is not recommended for pregnant patients during the second and third trimester taking atazanavir with both tenofovir DF and an H2RA. Hormonal contraceptives:ethinyl estradiol and norgestimate or norethindrone ethinyl estradiol -norgestimate -ethinyl estradiol -norethindrone Use with caution if coadministration of oral contraceptives with atazanavir or atazanavir with ritonavir. If atazanavir with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If atazanavir is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of atazanavir or atazanavir with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants:cyclosporine, sirolimus, tacrolimus -immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with atazanavir. Inhaled beta agonist:Salmeterol -salmeterol Coadministration of salmeterol with atazanavir is not recommended. Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid:fluticasone Atazanavir-fluticasone Atazanavir with ritonavir -fluticasone Concomitant use of fluticasone propionate and atazanavir (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Concomitant use of fluticasone propionate and atazanavir with ritonavir may increase plasma concentrations of fluticasone propionate, resulting 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 propionate. Coadministration of fluticasone propionate and atazanavir with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions 5.1)] Macrolide antibiotics:clarithromycin -clarithromycin 14-OH clarithromycin -atazanavir Increased concentrations of clarithromycin may cause QTc prolongations; therefore, dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium aviumcomplex. Coadministration of atazanavir with ritonavir and clarithromycin has not been studied. Opioids:buprenorphine -buprenorphine -norbuprenorphine Coadministration of buprenorphine and atazanavir with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of atazanavir with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and atazanavir with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and atazanavir without ritonavir may decrease atazanavir plasma concentrations. The coadministration of atazanavir and buprenorphine without ritonavir is not recommended. PDE5 inhibitors:sildenafil, tadalafil, vardenafil -sildenafil -tadalafil -vardenafil Coadministration with atazanavir has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of atazanavir with REVATIO (R)(sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications 4)] The following dose adjustments are recommended for the use of ADCIRCA (R)(tadalafil) with atazanavir: Coadministration of ADCIRCA (R)in patients on atazanavir (with or without ritonavir): .For patients receiving atazanavir (with or without ritonavir) for at least one week, start ADCIRCA (R)at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of atazanavir (with or without ritonavir) in patients on ADCIRCA (R): .Avoid the use of ADCIRCA (R)when starting atazanavir (with or without ritonavir). Stop ADCIRCA (R)at least 24 hours before starting atazanavir (with or without ritonavir). At least one week after starting atazanavir (with or without ritonavir), resume ADCIRCA (R)at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA (R)(sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS (R)(tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. Atazanavirwith ritonavir:Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Atazanavir:Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. Proton-pump inhibitors:omeprazole atazanavir Plasma concentrations of atazanavir were substantially decreased when atazanavir 400 mg or atazanavir 300 mg with ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily in adults, which may result in loss of therapeutic effect and development of resistance. In treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the atazanavir 300 mg with ritonavir 100 mg dose. In treatment-experienced adult patients:The use of PPIs in treatment-experienced patients receiving atazanavir is not recommended. For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 12.3). See Contraindications 4) Table for orally administered midazolam. In combination with atazanavir 300 mg and ritonavir 100 mg once daily. In combination with atazanavir 400 mg once daily. 7.4 Drugs With No Observed Interactions With Atazanavir. No clinically significant drug interactions were observed when atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 12.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17). Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or Subjects with HIV-1 Infection in the Fed State 400 mg once daily 300 mg with ritonavir 100 mg once daily HealthySubjects Subjects with HIV-1 Infection Healthy Subjects Subjects with HIV-1 Infection Parameter (n=14) (n=13) (n=28) (n=10) max (ng/mL) Geometric mean 5199 (26) 2298 (71) 6129 (31) 4422 (58) (CV%) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) max (h) Median 2.5 2.0 2.7 3.0 AUC (ngoh/mL) Geometric mean 28132 (28) 14874 (91) 57039 (37) 46073 (66) (CV%) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2) 8.6 (2.3) min (ng/mL) Geometric mean 159 (88) 120 (109) 1227 (53) 636 (97) (CV%) Mean (SD) 218 (191) 273 (298) 1441 (757) 862 (838) n=26. n=12. Figure displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200-mg capsules) with light meal and after atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with light meal in adult subjects with HIV-1 infection. Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Subjects with HIV-1 Infection Absorption Atazanavir is rapidly absorbed with T max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and max values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days and 8, with an accumulation of approximately 2.3 fold. Food Effect Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of single 400 mg dose of atazanavir with light meal (357 kcal, 8.2 fat, 10.6 protein) resulted in 70% increase in AUC and 57% increase in max relative to the fasting state. Administration of single 400 mg dose of atazanavir with high-fat meal (721 kcal, 37.3 fat, 29.4 protein) resulted in mean increase in AUC of 35% with no change in max relative to the fasting state. Administration of atazanavir with either light meal or high-fat meal decreased the coefficient of variation of AUC and max by approximately one-half compared to the fasting state. Coadministration of single 300 mg dose of atazanavir and 100 mg dose of ritonavir with light meal (336 kcal, 5.1 fat, 9.3 protein) resulted in 33% increase in the AUC and 40% increase in both the max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with high-fat meal (951 kcal, 54.7 fat, 35.9 protein) did not affect the AUC of atazanavir relative to fasting conditions and the max was within 11% of fasting values. The 24-hour concentration following high-fat meal was increased by approximately 33% due to delayed absorption; the median max increased from 2.0 to 5.0 hours. Coadministration of atazanavir with ritonavir with either light or high-fat meal decreased the coefficient of variation of AUC and max by approximately 25% compared to the fasting state. Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to similar extent (89% and 86%, respectively). In multiple-dose study in subjects with HIV-1 infection dosed with atazanavir 400 mg once daily with light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A. Elimination Following single 400 mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately hours at steady state following dose of 400 mg daily with light meal. Specific Populations Renal Impairment In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir max was 9% lower, AUC was 19% higher, and min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for max, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis see Dosage and Administration (2.7)]. Hepatic Impairment Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh and Child-Pugh subjects) after single 400 mg dose. The mean AUC(0 to was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)]. Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric subjects taking the capsule formulation were predicted by population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Subjects with HIV-1 Infection Body Weight(range in kg) atazanavir with ritonavir Dose (mg) max ng/mL Geometric Mean (CV%) AUC ngoh/mL Geometric Mean (CV%)C min ng/mL Geometric Mean (CV%) 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) >=35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 infection receiving atazanavir capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 Infection in the Fed StateAtazanavir 300 mg with ritonavir 100 mgPharmacokinetic Parameter2nd Trimester(n=5 a) 3rd Trimester(n=20)Postpartum (n=34)C max ng/mL 3078.85 3291.46 5721.21 Geometric mean (CV%) (50) (48) (31) AUC ngoh/mL 27657.1 34251.5 61990.4 Geometric mean (CV%) (43) (43) (32) min ng/mL 538.70 668.48 1462.59 Geometric mean (CV%) (46) (50) (45) Available data during the 2nd trimester are limited. Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4 to 12 weeks) than those observed historically in, non-pregnant patients with HIV-1 Infection. Atazanavir plasma trough concentrations were approximately 2.2-fold higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1 infection. C min is concentration 24 hours post-dose. Drug Interaction Data Atazanavir is metabolism-dependent CYP3A inhibitor, with K inact value of 0.05 to 0.06 min -1 and i value of 0.84 to 1.0 uM. Atazanavir is also direct inhibitor for UGT1A1 (K i=1.9 uM) and CYP2C8 (K i=2.1 uM). Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, max, and min are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs Coadministered DrugCoadministered DrugDose/ScheduleAtazanavir Dose/ScheduleRatio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/withoutCoadministered Drug; No Effect 1.00 CmaxAUCCmin atenolol 50 mg QD, 7-11 (n=19) and 19-23 400 mg QD, 1-11 (n=19) 1.00 (0.89, 1.12) 0.93 (0.85, 1.01) 0.74 (0.65, 0.86) clarithromycin 500 mg BID, 7-10 (n=29) and 18-21 400 mg QD, 1-10 (n=29) 1.06 (0.93, 1.20) 1.28 (1.16, 1.43) 1.91 (1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T) ddI: 200 mg dose, d4T: 40 mg dose (n=31) 400 mg dose simultaneously with ddI and d4T (n=31) 0.11 (0.06, 0.18) 0.13 (0.08, 0.21) 0.16 (0.10, 0.27) ddI: 200 mg dose, d4T: 40 mg dose (n=32) 400 mg dose h after ddI d4T (n=32) 1.12 (0.67, 1.18) 1.03 (0.64, 1.67) 1.03 (0.61, 1.73) efavirenz 600 mg QD, 7-20 (n=27) 400 mg QD, 1-20 (n=27) 0.41 (0.33, 0.51) 0.26 (0.22, 0.32) 0.07 (0.05, 0.10) 600 mg QD, 7-20 (n=13) 400 mg QD, 1-6 (n=23) then 300 mg with ritonavir 100 mg QD, h before efavirenz, 7-20 (n=13) 1.14 (0.83, 1.58) 1.39 (1.02, 1.88) 1.48 (1.24, 1.76) 600 mg QD, 11-24 (pm) (n=14) 300 mg QD with ritonavir 100 mg QD, 1-10 (pm) (n=22), then 400 mg QD with ritonavir 100 mg QD, 11-24 (pm), (simultaneously with efavirenz) (n=14) 1.1 (1.08, 1.27) 1.00 (0.91, 1.10) 0.58 (0.49, 0.69) famotidine 40 mg BID, 7-12 (n=15) 400 mg QD, 1-6 (n=45), 7-12 (simultaneous administration) (n=15) 0.53 (0.34, 0.82) 0.59 (0.40, 0.87) 0.58 (0.37, 0.89) 40 mg BID, 7-12 (n=14) 400 mg QD (pm), 1-6 (n=14), 7-12 (10 after, 12 before famotidine) (n=14) 1.08 (0.82, 1.41) 0.95 (0.74, 1.21) 0.79 (0.60, 1.04) 40 mg BID, 11-20 (n=14)c 300 mg QD with ritonavir 100 mg QD, 1-10 (n=46), 11-20d (simultaneous administration) (n=14) 0.86 (0.79, 0.94) 0.82 (0.75, 0.89) 0.72 (0.64, 0.81) 20 mg BID, 11-17 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 11-17 (am) (simultaneous administration with am famotidine) (n=18) d,e 0.91 (0.84, 0.99) 0.90 (0.82, 0.98) 0.81 (0.69, 0.94) 40 mg QD (pm), 18-24 (n=20) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 18-24 (am) (12 after pm famotidine) (n=20)e 0.89 (0.81, 0.97) 0.88 (0.80, 0.96) 0.77 (0.63, 0.93) 40 mg BID, 18-24 (n=18) 300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, 1-10 (am) (n=39), 18-24 (am) (10 after pm famotidine and h before am famotidine) (n=18)e 0.74 (0.66, 0.84) 0.79 (0.70, 0.88) 0.72 (0.63, 0.83) 40 mg BID, 11-20 (n=15) 300 mg QD with ritonavir 100 mg QD and 1-10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD, 11-20 (am) (n=15) 1.02 (0.87, 1.18) 1.03 (0.86, 1.22) 0.86 (0.68, 1.08) grazoprevir/ elbasvir grazoprevir 200 mg QD 1 35 (n 11) 300 mg QD with ritonavir 100 mg QD, 1- 35 (n 11) 1.12 (1.01, 1.24) 1.43 (1.30, 1.57) 1.23 (1.13, 1.34) elbasvir 50 mg QD 1 35 (n 8) 300 mg QD with ritonavir 100 mg QD, 1 35 (n 8) 1.02 (0.96, 1.08) 1.07 (0.98, 1.17) 1.15 (1.02, 1.29) ketoconazole 200 mg QD, 7-13 (n=14) 400 mg QD, 1-13 (n=14) 0.99 (0.77, 1.28) 1.10 (0.89, 1.37) 1.03 (0.53, 2.01) nevirapine f,g 200 mg BID, 1-23 (n=23) 300 mg QD with ritonavir 100 mg QD, 4-13, then 400 mg QD with ritonavir 100 mg QD, 14-23 (n=23)h 0.72 (0.60, 0.86) 1.02 (0.85, 1.24) 0.58 (0.48, 0.71) 0.81 (0.65, 1.02) 0.28 (0.20, 0.40) 0.41 (0.27, 0.60) omeprazole 40 mg QD, 7-12 (n=16) 400 mg QD, 1-6 (n=48), 7-12 (n=16) 0.04 (0.04, 0.05) 0.06 (0.05, 0.07) 0.05 (0.03, 0.07) 40 mg QD, 11-20 (n=15) 300 mg QD with ritonavir 100 mg QD, 1-20 (n=15) 0.28 (0.24, 0.32) 0.24 (0.21, 0.27) 0.22 (0.19, 0.26) 20 mg QD, 17-23 (am) (n=13) 300 mg QD with ritonavir 100 mg QD, 7-16 (pm) (n=27), 17-23 (pm) (n=13) j,k 0.61 (0.46, 0.81) 0.58 (0.44, 0.75) 0.54 (0.41, 0.71) 20 mg QD, 17-23 (am) (n=14) 300 mg QD with ritonavir 100 mg QD, 7-16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD, 17-23 (am) (n=14) l,m 0.69 (0.58, 0.83) 0.70 (0.57, 0.86) 0.69 (0.54, 0.88) pitavastatin mg QD for days 300 mg QD for days 1.13 (0.96, 1.32) 1.06 (0.90, 1.26) NA rifabutin 150 mg QD, 15-28 (n=7) 400 mg QD, 1-28 (n=7) 1.34 (1.14, 1.59) 1.15 (0.98, 1.34) 1.13 (0.68, 1.87) rifampin 600 mg QD, 17-26 (n=16) 300 mg QD with ritonavir 100 mg QD, 7-16 (n=48), 17-26 (n=16) 0.47 (0.41, 0.53) 0.28 (0.25, 0.32) 0.02 (0.02, 0.03) ritonavirn 100 mg QD, 11-20 (n=28) 300 mg QD, 1-20 (n=28) 1.86 (1.69, 2.05) 3.38 (3.13, 3.63) 11.89 (10.23, 13.82) tenofovir DFo 300 mg QD, 9-16 (n=34) 400 mg QD, 2-16 (n=34) 0.79 (0.73, 0.86) 0.75 (0.70, 0.81) 0.60 (0.52, 0.68) 300 mg QD, 15-42 (n=10) 300 mg with ritonavir 100 mg QD, 1-42 (n=10) 0.72p (0.50, 1.05) 0.75p (0.58, 0.97) 0.77p (0.54, 1.10) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, 2-3, 22-30; 400 mg BID, 1, 21 (n=20) 300 mg with ritonavir 100 mg QD, 11-30 (n=20) 0.87 (0.80, 0.96) 0.88 (0.82, 0.95) 0.80 (0.72, 0.90) voriconazole (Subjects without functional CYP2C19 allele) 50 mg BID, 2-3, 22-30; 100 mg BID, 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, 11-30 (n=8) 0.81 (0.66, 1.00) 0.80 (0.65, 0.97) 0.69 (0.54, 0.87) Data provided are under fed conditions unless otherwise noted. All drugs were given under fasted conditions. Atazanavir 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean max that was similar and AUC and min values that were 1.79 -and 4.46-fold higher relative to atazanavir 400 mg once daily alone. Similar results were noted when famotidine 20 mg BID was administered hours after and 10 hours before atazanavir 300 mg and ritonavir 100 mg and tenofovir DF 300 mg. Coadministration of atazanavir with ritonavir and tenofovir DF was administered after light meal. Study was conducted in subjects with HIV-1 infection. Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 1.42 (0.98, 2.05), 1.64 (1.11, 2.42), and 1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg; and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg. Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine. Subjects were treated with nevirapine prior to study entry. Omeprazole 40 mg was administered on an empty stomach hours before atazanavir. Omeprazole 20 mg was administered 30 minutes prior to light meal in the morning and atazanavir 300 mg with ritonavir 100 mg in the evening after light meal, separated by 12 hours from omeprazole. Atazanavir 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir geometric mean AUC (10%) and min (2.4-fold), with decrease in max (29%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1-6). Omeprazole 20 mg was given 30 minutes prior to light meal in the morning and atazanavir 400 mg with ritonavir 100 mg once daily after light meal, hour after omeprazole. Effects on atazanavir concentrations were similar when atazanavir 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. Atazanavir 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric mean AUC (32%) and min (3.3-fold), with decrease in Cmax (26%) relative to atazanavir 400 mg once daily in the absence of omeprazole (study days 1-6). Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir geometric mean values of max, AUC, and min by 18%, 103%, and 671%, respectively. Note that similar results were observed in studies where administration of tenofovir DF and atazanavir was separated by 12 hours. Ratio of atazanavir with ritonavir with tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnoteo). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: max 3190 ng/mL, AUC 34459 ngoh/mL, and Cmin 491 ng/mL. Study was conducted in subjects with HIV-1 infection. NA not available. Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Atazanavir Coadministered DrugCoadministered Drug Dose/ScheduleAtazanavir Dose/ScheduleRatio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without atazanavir; No Effect 1.00CmaxAUCCmin acetaminophen gm BID, 1-20 (n=10) 300 mg QD with ritonavir 100 mg QD, 11-20 (n=10) 0.87 (0.77, 0.99) 0.97 (0.91, 1.03) 1.26 (1.08, 1.46) atenolol 50 mg QD, 7-11 (n=19) and 19-23 400 mg QD, 1-11 (n=19) 1.34 (1.26, 1.42) 1.25 (1.16, 1.34) 1.02 (0.88, 1.19) clarithromycin 500 mg BID, 7-10 (n=21) and 18-21 400 mg QD, 1-10 (n=21) 1.50 (1.32, 1.71) OH- clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16) OH-clarithromycin: 0.30 (0.26, 0.34) 2.60 (2.35, 2.88) OH-clarithromycin: 0.38 (0.34, 0.42) ddI (entericcoated [EC] capsules)b 400 mg 1 (fasted), 8 (fed) (n=34) 400 mg QD, 2-8 (n=34) 0.64 (0.55, 0.74) 0.66 (0.60, 0.74) 1.13 (0.91, 1.41) 400 mg 1 (fasted), 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, 9-19 (n=31) 0.62 (0.52, 0.74) 0.66 (0.59, 0.73) 1.25 (0.92, 1.69) diltiazem 180 mg QD, 7-11 (n=28) and 19-23 400 mg QD, 1-11 (n=28) 1.98 (1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25 (2.09, 2.16) desacetyl-diltiazem: 2.65 (2.45, 2.87) 2.42 (2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42) ethinyl estradiol norethindronec Ortho-Novum (R) 7/7/7 QD, 1-29 (n=19) 400 mg QD, 16-29 (n=19) ethinyl estradiol: 1.15 (0.99, 1.32) norethindrone: 1.67 (1.42, 1.96) ethinyl estradiol: 1.48 (1.31, 1.68) norethindrone: 2.10 (1.68, 2.62) ethinyl estradiol: 1.91 (1.57, 2.33) norethindrone: 3.62 (2.57, 5.09) ethinyl estradiol norgestimate Ortho Tri-Cyclen (R) QD, 1-28 (n=18), then Ortho Tri- Cyclen (R) LO QD, 29-42e (n=14) 300 mg QD with ritonavir 100 mg QD, 29-42 (n=14) ethinyl estradiol: 0.84 (0.74, 0.95) 17-deacetyl norgestimate: 1.68 (1.51, 1.88) ethinyl estradiol: 0.81 (0.75, 0.87) 17-deacetyl norgestimate: 1.85 (1.67, 2.05) ethinyl estradiol: 0.63 (0.55, 0.71) 17-deacetyl norgestimate :f 2.02 (1.77, 2.31) glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) >=4.06g(3.15, 5.23) >=6.53g(5.24, 8.14) >=14.3 (9.85, 20.7) 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD (n=12) >=1.29g (1.15, 1.45) >=1.64g (1.48, 1.82) >=2.29 (1.95, 2.68) grazoprevir/ elbasvir grazoprevir 200 mg QD 1 35 (n=12) 300 mg QD with ritonavir 100 mg QD 1 35 (n=12) 6.24 (4.42, 8.81) 10.58 (7.78, 14.39) 11.64 (7.96, 17.02) elbasvir 50 mg QD 1 35 (n=10) 300 mg QD with ritonavir 100 mg QD 1 35 (n=10) 4.15 (3.46, 4.97) 4.76 (4.07, 5.56) 6.45 (5.51, 7.54) methadone Stable maintenance dose, 1-15 (n=16) 400 mg QD, 2-15 (n=16) (R)-methadone 0.91 (0.84, 1.0) total: 0.85 (0.78, 0.93) (R)-methadone 1.03 (0.95, 1.10) total: 0.94 (0.87, 1.02) (R)-methadone 1.11 (1.02, 1.20) total: 1.02 (0.93, 1.12) nevirapine i,j 200 mg BID, 1-23 (n=23) 300 mg QD with ritonavir 100 mg QD, 4-13, then 400 mg QDwith ritonavir 100 mg QD, 14-23 (n=23) 1.17 (1.09, 1.25) 1.21 (1.11, 1.32) 1.25 (1.17, 1.34) 1.26 (1.17, 1.36) 1.32 (1.22, 1.43) 1.35 (1.25, 1.47) omeprazolek 40 mg single dose, 7 and 20 (n=16) 400 mg QD, 1-12 (n=16) 1.24 (1.04, 1.47) 1.45 (1.20, 1.76) NA rifabutin 300 mg QD, 1-10 then 150 mg QD, 11-20 (n=3) 600 mg QD, d 11-20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl- rifabutin: 8.20 (5.90, 11.40) 2.10 (1.57, 2.79) 25-O-desacetyl- rifabutin: 22.01 (15.97, 30.34) 3.43 (1.98, 5.96) 25-O-desacetyl- rifabutin: 75.6 (30.1, 190.0) 150 mg twice weekly, 1-15 (n=7) 300 mg QDwith ritonavir 100 mg QD, 1-17 (n=7) 2.49m (2.03, 3.06) 25-O-desacetyl- rifabutin: 7.77 (6.13, 9.83) 1.48m (1.19, 1.84) 25-O-desacetyl- rifabutin: 10.90 (8.14, 14.61) 1.40m (1.05, 1.87) 25-O-desacetyl- rifabutin: 11.45 (8.15, 16.10) pitavastatin mg QD for days 300 mg QD for days 1.60 (1.39, 1.85) 1.31 (1.23, 1.39) NA rosiglitazonen mg single dose, 1, 7, 17 (n=14) 400 mg QD, 2-7, then 300 mg QDwith ritonavir 100 mg QD, 8-17 (n=14) 1.08 (1.03, 1.13) 0.97 (0.91, 1.04) 1.35 (1.26, 1.44) 0.83 (0.77, 0.89) NA NA rosuvastatin 10 mg single dose 300 mg QDwith ritonavir 100 mg QD for days 7-foldo 3-foldo NA saquinavir p(soft gelatin capsules) 1200 mg QD, 1-13 (n=7) 400 mg QD, 7-13 (n=7) 4.39 (3.24, 5.95) 5.49 (4.04, 7.47) 6.86 (5.29, 8.91) sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mgwith 100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA 100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA 100 mg voxilaprevir single dose (n=15) 300 mgwith 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA tenofovir DFq 300 mg QD, 9-16 (n=33) and 24-30 (n=33) 400 mg QD, d2-16 (n=33) 1.14 (1.08, 1.20) 1.24 (1.21, 1.28) 1.22 (1.15, 1.30) 300 mg QD, 1-7 (pm) (n=14) 25-34 (pm) (n=12) 300 mg QDwith ritonavir 100 mg QD, 25-34 (am) (n=12)r 1.34 (1.20, 1.51) 1.37 (1.30, 1.45) 1.29 (1.21, 1.36) voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID, 2-3, 22-30; 400 mg BID, 1, 21 (n=20) 300 mgwith ritonavir 100 mg QD, 11-30 (n=20) 0.90 (0.78, 1.04) 0.67 (0.58, 0.78) 0.61 (0.51, 0.72) voriconazole (Subjects without functional CYP2C19 allele) 50 mg BID, 2-3, 22-30; 100 mg BID, 1, 21 (n=8) 300 mg with ritonavir 100 mg QD, 11-30 (n=8) 4.38 (3.55, 5.39) 5.61 (4.51, 6.99) 7.65 (5.71, 10.2) lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, 1-12 (n=19) 400 mg QD, 7-12 (n=19) lamivudine: 1.04 (0.92, 1.16) zidovudine: 1.05 (0.88, 1.24) zidovudine glucuronide: 0.95 (0.88, 1.02) lamivudine: 1.03 (0.98, 1.08) zidovudine: 1.05 (0.96, 1.14) zidovudine glucuronide: 1.00 (0.97, 1.03) lamivudine: 1.12 (1.04, 1.21) zidovudine: 0.69 (0.57, 0.84) zidovudine glucuronide: 0.82 (0.62, 1.08) Data provided are under fed conditions unless otherwise noted. 400 mg ddI EC and atazanavir were administered together with food on Days and 19. Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively. Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for max, AUC, and min were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively. All subjects were on 28-day lead-in period; one full cycle of Ortho Tri-Cyclen (R). Ortho Tri-Cyclen (R) contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen (R) LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg. 17-deacetyl norgestimate is the active component of norgestimate. Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported. (R)-methadone is the active isomer of methadone. Study was conducted subjects with HIV-1 infection. Subjects were treated with nevirapine prior to study entry. Omeprazole was used as metabolic probe for CYP2C19. Omeprazole was given hours after atazanavir on Day 7; and was given alone hours after light meal on Day 20. Not the recommended therapeutic dose of atazanavir. When compared to rifabutin 150 mg QD alone d1-10 (n=14). Total of rifabutin 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69). Rosiglitazone used as probe substrate for CYP2C8. Mean ratio (with/without coadministered drug). indicates an increase in rosuvastatin exposure. The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID. Note that similar results were observed in study where administration of tenofovir DF and atazanavir was separated by 12 hours. Administration of tenofovir DF and atazanavir was temporally separated by 12 hours. NA not available.. 12 before famotidine) atazanavircapsulecamberfigure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. 8.1) Lactation: Breastfeeding is not recommended. 8.2) Hepatitis or co-infection: Monitor liver enzymes. 5.4, 6.1) Renal impairment: Atazanavir is not recommended for use in treatment- experienced patients with end-stage renal disease managed with hemodialysis. 2.7, 8.7) Hepatic impairment: Atazanavir is not recommended in patients with severe hepatic impairment. Atazanavir with ritonavir is not recommended in patients with any degree of hepatic impairment. 2.8, 8.8) 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to atazanavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryAtazanavir has been evaluated in limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7 to 1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data]. Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period Atazanavir must be administered with ritonavir in pregnant patients. For pregnant patients, no dosage adjustment is required for atazanavir with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an 2-receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend atazanavir dose for use with both an 2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first months after delivery [see Dosage and Administration 2.6) and Clinical Pharmacology 12.3)]. Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir [see Warnings and Precautions 5.8)] including those who are pregnant [see Data]. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data]. Data Human Data In clinical trial AI424-182, atazanavir with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir with ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1 infection, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and less than 38 weeks gestation) had bilirubin levels of mg/dL or greater within the first day of life. Lack of ethnic diversity was study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is to 4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level. 8.2 Lactation. Risk Summary The Centers for Disease Control and Prevention recommend that patients with HIV-1 infection, not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed. 8.3 Nursing Mothers. 8.4 Pediatric Use. Atazanavir is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, years of age and older weighing at least 15 kg. Atazanavir is not recommended for use in pediatric patients below the age of months due to the risk of kernicterus [see Indications and Usage 1)]. All atazanavir contraindications, warnings, and precautions apply to pediatric patients [see Contraindications 4) and Warnings and Precautions 5)]. The safety, pharmacokinetic profile, and virologic response of atazanavir in pediatric patients at least years of age and older weighing at least 15 kg were established in an open-label, multicenter clinical trial: PACTG 1020A [see Clinical Pharmacology 12.3) and Clinical Studies 14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions 6.1)] See Dosage and Administration 2.4) for dosing recommendations for the use of atazanavir capsules. 8.5 Geriatric Use. Clinical studies of atazanavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on comparison of mean single-dose pharmacokinetic values for max and AUC, dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Age/Gender. study of the pharmacokinetics of atazanavir was performed in young (n=29; 18 to 40 years) and elderly (n=30; >65 years) healthy subjects. There were no clinically significant pharmacokinetic differences observed due to age or gender. 8.7 Impaired Renal Function. Atazanavir is not recommended for use in treatment-experienced patients with HIV-1 infection, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration 2.7) and Clinical Pharmacology 12.3)]. 8.8 Impaired Hepatic Function. Atazanavir is not recommended for use in patients with severe hepatic impairment. Atazanavir with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration 2.8) and Clinical Pharmacology 12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. 5.1, 7.3, 12.2, 17) Severe Skin Reactions: Discontinue if severe rash develops. 5.2, 17) Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If concomitant transaminase increase occurs, evaluate for alternative etiologies. 5.8) Hepatotoxicity: Patients with hepatitis or infection are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. 2.8, 5.4, 8.8) Chronic kidney disease has been reported during postmarketing surveillance in HIV-1 infection treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of atazanavir in patients with progressive renal disease. 5.5) Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. 5.6) The concomitant use of atazanavir with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. 5.7, 7.3) Patients receiving atazanavir may develop new onset or exacerbations of diabetes mellitus/hyperglycemia 5.9), immune reconstitution syndrome (5.10), and redistribution/accumulation of body fat 5.11). Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. 5.12) 5.1Cardiac Conduction Abnormalities. Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities see Adverse Reactions 6.2) and Overdosage 10) ]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir-treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients see Clinical Pharmacology 12.2)]. 5.2Severe Skin Reactions. In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection treated with atazanavir. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at rate of >=2%) are presented for the individual clinical studies see Adverse Reactions 6.1) ]. Dosing with atazanavir was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir see Contraindications 4) and Adverse Reactions 6.1) ]. Atazanavir should be discontinued if severe rash develops. 5.4Hepatotoxicity. Patients with underlying hepatitis or viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with atazanavir and during treatment see Dosage and Administration 2.2), Adverse Reactions 6.1), and Use in Specific Populations 8.8) ]. 5.5 Chronic Kidney Disease. Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with atazanavir and continued during treatment with atazanavir. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. In patients with progressive kidney disease, discontinuation of atazanavir may be considered see Dosage and Administration 2.2 and 2.7) and Adverse Reactions 6.2) ]. 5.6 Nephrolithiasis and Cholelithiasis. Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered see Adverse Reactions 6.2) ]. 5.7 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of atazanavir with ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving atazanavir with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of atazanavir with 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 atazanavir with ritonavir. loss of therapeutic effect of atazanavir with ritonavir and possible development of resistance. See Table 16 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 containing atazanavir with ritonavir; and monitor for the adverse reactions associated with the concomitant medications see Contraindications 4) and Drug Interactions 7) ]. 5.8 Hyperbilirubinemia. Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established see Adverse Reactions 6.1) ]. 5.9 Diabetes Mellitus/Hyperglycemia. New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-1 infection 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 relationship between protease inhibitor therapy and these events has not been established [see Adverse Reactions 6.2)]. 5.10 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.11 Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.12 Hemophilia. There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type and treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. causal relationship between protease inhibitor therapy and these events has not been established.. 5.13 Resistance/Cross-Resistance. Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors see Microbiology 12.4) ].