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 REYATAZ 400 mg once daily and after administration of REYATAZ 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 Statea n=26. n=12.400 mg once daily300 mg with ritonavir100 mg once dailyParameterHealthySubjects(n=14)Subjects with HIV-1 Infection(n=13)HealthySubjects(n=28)Subjects with HIV-1 Infection(n=10)Cmax (ng/mL) Geometric mean (CV%)5199 (26)2298 (71)6129 (31)4422 (58) Mean (SD)5358 (1371)3152 (2231)6450 (2031)5233 (3033)Tmax (h) Median2.52.02.73.0AUC (ngoh/mL) Geometric mean (CV%)28132 (28)14874 (91)57039 (37)46073 (66) 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)a 8.6 (2.3)Cmin (ng/mL) Geometric mean (CV%)159 (88)120 (109)1227 (53)636 (97) Mean (SD)218 (191)273 (298)b 1441 (757)862 (838)Figure displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with light meal and after REYATAZ 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 Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax 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 REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of single 400-mg dose of REYATAZ with light meal (357 kcal, 8.2 fat, 10.6 protein) resulted in 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of single 400-mg dose of REYATAZ with high-fat meal (721 kcal, 37.3 fat, 29.4 protein) resulted in mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.Coadministration of single 300-mg dose of REYATAZ 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 Cmax 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 Cmax 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 Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either light or high-fat meal decreased the coefficient of variation of AUC and Cmax 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 REYATAZ 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. REYATAZ 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 Cmax was 9% lower, AUC was 19% higher, and Cmin 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 Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ 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 REYATAZ 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-) 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. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ 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 powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5) ].Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Subjects with HIV-1Body Weight(range in kg) [n]atazanavir with ritonavirDose (mg)Cmax ng/mLGeometric Mean(CV%)AUC ngoh/mLGeometric Mean(CV%)Cmin ng/mLGeometric Mean(CV%)5 to <10 [20]150/804131 (55%)32503 (61%)336 (76%)5 to <10 [10]200/804466 (59%)39519 (54%)550 (60%)10 to <15 [18]200/805197 (53%)50305 (67%)572 (111%)15 to <25 [32]250/805394 (46%)55687 (45%)686 (68%)25 to <35 [8]300/1004209 (52%)44329 (63%)468 (104%)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 InfectionBody Weight(range in kg)atazanavir with ritonavirDose (mg)Cmax ng/mLGeometric Mean(CV%)AUC ngoh/mLGeometric Mean(CV%)Cmin ng/mLGeometric Mean(CV%)15 to <35200/1003303 (86%)37235 (84%)538 (99%)>=35300/1002980 (82%)37643 (83%)653 (89%). Pregnancy The pharmacokinetic data from pregnant women with HIV-1 infection receiving REYATAZ 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 Statea 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 (4-12 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. Cmin is concentration 24 hours post-dose.Atazanavir 300 mg with ritonavir 100 mgPharmacokinetic Parameter2nd Trimester(n=5a)3rd Trimester(n=20)Postpartumb (n=34)Cmax ng/mL Geometric mean (CV%)3078.85(50)3291.46(48)5721.21(31)AUC ngoh/mL Geometric mean (CV%)27657.1(43)34251.5(43)61990.4(32)Cmin ng/mLc Geometric mean (CV%)538.70(46)668.48(50)1462.59(45). Drug Interaction Data Atazanavir is metabolism-dependent CYP3A inhibitor, with Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 uM. Atazanavir is also direct inhibitor for UGT1A1 (Ki=1.9 uM) and CYP2C8 (Ki=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, REYATAZ 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 REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin 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). REYATAZ did not have significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa CoadministeredDrugCoadministered DrugDose/ScheduleREYATAZDose/ScheduleRatio (90% Confidence Interval) of AtazanavirPharmacokinetic Parameters with/withoutCoadministered Drug;No Effect 1.00Cmax AUCCmin Data provided are under fed conditions unless otherwise noted. All drugs were given under fasted conditions. REYATAZ 300 mg with ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to REYATAZ 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 with 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 Cmax, AUC, and Cmin 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 REYATAZ. Omeprazole 20 mg was administered 30 minutes prior to light meal in the morning and REYATAZ 300 mg with ritonavir 100 mg in the evening after light meal, separated by 12 hours from omeprazole. REYATAZ 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 Cmin (2.4-fold), with decrease in Cmax (29%) relative to REYATAZ 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 REYATAZ 400 mg with ritonavir 100 mg once daily after light meal, hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. REYATAZ 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 Cmin (3.3-fold), with decrease in Cmax (26%) relative to REYATAZ 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 Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours. Ratio of atazanavir with ritonavir and tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax 3190 ng/mL, AUC 34459 ngoh/mL, and Cmin 491 ng/mL. Study was conducted in subjects with HIV-1 infection.NA not available.atenolol50 mg QD, 7-11 (n=19)and 19-23400 mg QD, 1-11(n=19)1.00(0.89, 1.12)0.93(0.85, 1.01)0.74(0.65, 0.86)clarithromycin500 mg BID, 7-10 (n=29)and 18-21400 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)b ddI: 200 mg 1 dose,d4T: 40 mg 1 dose (n=31)400 mg 1 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 1 dose,d4T: 40 mg 1 dose (n=32)400 mg 1 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)efavirenz600 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,2 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,d 1-10 (pm) (n=22),then 400 mg QD with ritonavir 100 mg QD, 11-24 (pm), (simultaneously with efavirenz)(n=14)1.17(1.08, 1.27)1.00(0.91, 1.10)0.58(0.49, 0.69)famotidine40 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),d 7-12 (10 after, h 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,d 1-10 (n=46),d 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,d 1-10 (am) (n=39),d 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,d 1-10 (am)(n=39),d 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),d 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, 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/elbasvirgrazoprevir 200 mg QDd 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 QDd 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)ketoconazole200 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)nevirapinef,g 200 mg BID, 1-23(n=23)300 mg QD with ritonavir 100 mg QD,d 4-13, then400 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)omeprazole40 mg QD, 7-12(n=16)i 400 mg QD,d 1-6 (n=48),d 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)i 300 mg QD with ritonavir 100 mg QD,d 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,d 7-16 (pm) (n=27),d 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,d 7-16 (am) (n=27), then400 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)pitavastatin4 mg QD for days300 mg QD for days1.13(0.96, 1.32)1.06(0.90, 1.26)NArifabutin150 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)rifampin600 mg QD, 17-26(n=16)300 mg QD with ritonavir 100 mg QD,d 7-16 (n=48),d 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)Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa CoadministeredDrugCoadministered DrugDose/ScheduleREYATAZDose/ScheduleRatio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/withoutREYATAZ;No Effect 1.00Cmax AUCCmin Data provided are under fed conditions unless otherwise noted. 400 mg ddI EC and REYATAZ 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 Cmax, AUC, and Cmin 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 Cmax, AUC, and Cmin 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 in 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 REYATAZ 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 and 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 Cmax 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 REYATAZ was separated by 12 hours. Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours.NA not available.acetaminophen1 BID, 1-20(n=10)300 mg QD with ritonavir 100 mg QD,d 11-20 (n=10)0.87(0.77, 0.99)0.97(0.91, 1.03)1.26(1.08, 1.46)atenolol50 mg QD, 7-11 (n=19)and 19-23400 mg QD, 1-11(n=19)1.34(1.26, 1.42)1.25(1.16, 1.34)1.02(0.88, 1.19)clarithromycin500 mg BID, 7-10 (n=21)and 18-21400 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 (enteric-coated [EC] capsules)b 400 mg 1 (fasted), 8 (fed)(n=34)400 mg QD,d 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)diltiazem180 mg QD, 7-11 (n=28)and 19-23400 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,d 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 norgestimated 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,d 29-42(n=14)ethinyl estradiol:0.84(0.74, 0.95)17-deacetyl norgestimate:f 1.68(1.51, 1.88)ethinyl estradiol:0.81(0.75, 0.87)17-deacetylnorgestimate:f 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/ pibrentasvir300 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)>=14.3g (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)>=2.29g (1.95, 2.68)grazoprevir/elbasvirgrazoprevir 200 mg QD 1-35(n=12)300 mg QD with ritonavir 100 mg QDd 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 QDd 1-35(n=10)300 mg QD with ritonavir 100 mg QDd 1-35(n=10)4.15 (3.46, 4.97)4.76 (4.07, 5.56)6.45(5.51, 7.54)methadoneStable maintenancedose, 1-15(n=16)400 mg QD, 2-15(n=16)(R)-methadoneh 0.91(0.84, 1.0)total: 0.85(0.78, 0.93)(R)-methadoneh 1.03(0.95, 1.10)total: 0.94(0.87, 1.02)(R)-methadoneh 1.11(1.02, 1.20)total: 1.02(0.93, 1.12)nevirapinei,j 200 mg BID, 1-23(n=23)300 mg QD with ritonavir 100 mg QD,d 4-13, then400 mg QD with ritonavir 100 mg QD,d 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)NArifabutin300 mg QD, 1-10then 150 mg QD, 11-20(n=3)600 mg QD,l 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 QD with ritonavir 100 mg QD,d 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)pitavastatin4 mg QDfor days300 mg QDfor days1.60(1.39, 1.85)1.31(1.23, 1.39)NArosiglitazonen mg single dose, 1, 7, 17(n=14)400 mg QD, 2-7, then300 mg QD with ritonavir 100 mg QD,d 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 NArosuvastatin10 mg single dose300 mg QD with ritonavir 100 mg QD for days 7-foldo 3-foldo NAsaquinavirp (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/voxilaprevir400 mg sofosbuvir single dose(n=15)300 mg with 100 mg ritonavir single dose(n=15)1.29(1.09, 1.52)sofosbuvir metaboliteGS-3310071.05(0.99, 1.12)1.40(1.25, 1.57)sofosbuvir metaboliteGS-3310071.25(1.16, 1.36)NA100 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)NA100 mg voxilaprevir single dose(n=15)300 mg with 100 mg ritonavir single dose(n=15)4.42(3.65, 5.35)4.31(3.76, 4.93)NAtenofovir DFq 300 mg QD, 9-16 (n=33)and 24-30(n=33)400 mg QD, 2-16(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)d 25-34 (pm) (n=12)300 mg QD with 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 mg with 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 zidovudine150 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)zidovudineglucuronide: 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). Reyataz Fig 1. 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 (EC50) 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 EC50 values above the EC50 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 REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 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 Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Subjectsa 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. Mixture of I50I/L emerged in other atazanavir 400 mg-treated subjects. Neither isolate was phenotypically resistant to atazanavir.REYATAZ 300 mgwithritonavir 100 mg(n=95)REYATAZ 400 mg(n=105)Virologic Failure (>=50 copies/mL) at Week 9615 (16%)34 (32%)Virologic Failure with Genotypes and Phenotypes Data 517Virologic Failure Isolates with atazanavir-resistance at Week 960/5 (0%)b 4/17 (24%)b Virologic Failure Isolates with I50L Emergence at Week 96c 0/5 (0%)b 2/17 (12%)b Virologic Failure Isolates with Lamivudine Resistance at Week 962/5 (40%)b 11/17 (65%)b Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 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 subject 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/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 REYATAZ 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive subjects who experienced virologic failure on REYATAZ 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 1-2 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 Analysisa 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.Virologic Response HIV-1 RNA <400 copies/mLb Number and Type of Baseline PISubstitutionsa atazanavir with ritonavir(n=110)lopinavir/ritonavirc (n=113)3 or more primary PI substitutions includingd: D30N75% (6/8)50% (3/6) M36I/V19% (3/16)33% (6/18) M46I/L/T24% (4/17)23% (5/22) I54V/L/T/M/A31% (5/16)31% (5/16) A71V/T/I/G34% (10/29)39% (12/31) G73S/A/C/T14% (1/7)38% (3/8) V77I47% (7/15)44% (7/16) V82A/F/T/S/I29% (6/21)27% (7/26) I84V/A11% (1/9)33% (2/6) N88D63% (5/8)67% (4/6) L90M10% (2/21)44% (11/25)Number of baseline primary PI substitutionsa All patients, as-treated58% (64/110)59% (67/113)0-2 PI substitutions75% (50/67)75% (50/67)3-4 PI substitutions41% (14/34)43% (12/28)5 or more PI substitutions0% (0/9)28% (5/18)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 REYATAZ.Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Subjects in Study AI424-045, As-Treated AnalysisVirologic Response HIV RNA <400 copies/mLb Baseline Phenotypea atazanavir with ritonavir(n=111)lopinavir/ritonavirc (n=111)a 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. 0-271% (55/78)70% (56/80) >2-553% (8/15)44% (4/9) >5-1013% (1/8)33% (3/9) >1010% (1/10)23% (3/13).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS . Coadministration of REYATAZ 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 REYATAZ to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ 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 REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ 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 REYATAZ 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 REYATAZ Atazanavir is CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZs 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 REYATAZ [see Dosage and Administration 2.3, 2.4, 2.5 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 REYATAZ. 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 Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)Concomitant Drug Class:Specific DrugsEffect on Concentration of Atazanavir or Concomitant DrugClinical Commenta 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 with ritonavir 100 mg once daily. In combination with atazanavir 400 mg once daily.HIV Antiviral AgentsNucleoside Reverse Transcriptase Inhibitors (NRTIs):didanosine buffered formulationsenteric-coated (EC) capsules atazanavir didanosineCoadministration of REYATAZ with didanosine buffered tablets resulted in marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) h before or h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.Nucleotide Reverse Transcriptase Inhibitors:tenofovir disoproxil fumarate (DF) atazanavir tenofovirTenofovir DF may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as single daily dose with food). REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6).Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs):efavirenz atazanavirEfavirenz decreases atazanavir exposure.In treatment-naive adult patients:If REYATAZ is combined with efavirenz, REYATAZ 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 REYATAZ with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure.nevirapine atazanavir nevirapineCoadministration of REYATAZ 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) saquinavirAppropriate 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 REYATAZ 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)].indinavirCoadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)].ritonavir atazanavirIf REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 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 inhibitorAlthough not studied, the coadministration of REYATAZ 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 grazoprevirCoadministration of REYATAZ 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 pibrentasvirCoadministration of REYATAZ 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 voxilaprevirCoadministration with REYATAZ is not recommended.Other AgentsAlpha 1-Adrenoreceptor Antagonist: alfuzosin alfuzosinCoadministration of REYATAZ with alfuzosin is contraindicated. The resulting increase in alfuzosin plasma concentrations can lead to hypotension [see Contraindications (4)].Antacids and buffered medications atazanavirReduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered hours before or hour after these medications.Antiarrhythmics:amiodarone, quinidineamiodarone, bepridil, lidocaine (systemic), quinidine amiodarone, bepridil, lidocaine (systemic), quinidineConcomitant use of REYATAZ 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 REYATAZ has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. Anticoagulants:warfarin warfarinCoadministration with REYATAZ 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 Oral Anticoagulants: betrixaban, dabigatran, edoxaban betrixaban dabigatran edoxabanConcomitant use of REYATAZ 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.rivaroxabanREYATAZ with ritonavir rivaroxabanCoadministration of REYATAZ with ritonavir and rivaroxaban is not recommended. Concomitant treatment with agents that are combined P- glycoprotein (P-gp) strong CYP3A4 inhibitors, such as ritonavir, increase exposure to rivaroxaban and may increase risk of bleeding.REYATAZ rivaroxabanCoadministration of REYATAZ, CYP3A4 inhibitor, and rivaroxaban may result in increased increase exposure to rivaroxaban and may increase risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban.apixabanREYATAZ with ritonavir apixabanConcomitant use of REYATAZ 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.REYATAZ apixabanConcomitant use of REYATAZ, 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 REYATAZ.Antidepressants:tricyclic antidepressants tricyclic antidepressantsCoadministration with REYATAZ 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 REYATAZ.trazodone trazodoneConcomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with CYP3A4 inhibitor such as REYATAZ, 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 REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning REYATAZ 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 REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, dose adjustment of phenytoin or phenobarbital may be required.lamotrigine lamotrigine Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations, and may require dosage adjustment of lamotrigine. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.Antifungals:ketoconazole, itraconazoleREYATAZ with ritonavir: ketoconazole itraconazoleCoadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir.voriconazoleREYATAZ with ritonavir in subjects with functional CYP2C19 allele: voriconazole atazanavir REYATAZ with ritonavir in subjects without functional CYP2C19 allele: voriconazole atazanavir The use of voriconazole in patients receiving REYATAZ 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 REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.Antigout:colchicine colchicineThe coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended.Recommended adult dosage of colchicine when administered with REYATAZ: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 twice day, the regimen should be adjusted to 0.3 mg once day. If the original regimen was 0.6 mg once day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice day). Antimycobacterials: rifampin atazanavirCoadministration of REYATAZ 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 rifabutinA 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 irinotecanCoadministration of REYATAZ 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 pimozideCoadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)] lurasidoneREYATAZ with ritonavir lurasidoneREYATAZ with ritonavirCoadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)].REYATAZ lurasidoneREYATAZ without ritonavirIf coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.quetiapine quetiapineInitiation of REYATAZ 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 taking REYATAZ with ritonavir:Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.Benzodiazepines:midazolam (oral)triazolam midazolam triazolamCoadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. REYATAZ 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 midazolamb midazolamConcomitant use of parenteral midazolam with REYATAZ 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-diltiazemCaution is warranted. dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied.felodipine, nifedipine, nicardipine, and verapamil calcium channel blockerCaution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.Endothelin receptor antagonists:bosentan atazanavir bosentanPlasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.Coadministration of bosentan in adult patients on REYATAZ with ritonavir: For patients who have been receiving REYATAZ 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 REYATAZ with ritonavir in adult patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ 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 derivativesCoadministration of REYATAZ 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 cisaprideCoadministration of REYATAZ 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) atazanavirCoadministration of products containing St. Johns wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)]. Lipid-modifying agentsHMG-CoA reductase inhibitors: lovastatin, simvastatin lovastatin simvastatinCoadministration of REYATAZ 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 rosuvastatinTitrate 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 REYATAZ, are used in combination with these drugs.Other Lipid Modifying Agents: lomitapide lomitapideCoadministration of REYATAZ 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 antagonists atazanavirPlasma concentrations of atazanavir were substantially decreased when REYATAZ 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:REYATAZ 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 H2-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 REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. ORFor patients unable to tolerate ritonavir, REYATAZ 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 REYATAZ without ritonavir in pregnant patients is not recommended.In treatment-experienced adult patients:Whenever an H2RA is given to patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.oREYATAZ 300 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with an H2RA.oREYATAZ 400 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with both tenofovir DF and an H2RA.oREYATAZ 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. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA.Hormonal contraceptives:ethinyl estradiol and norgestimate or norethindrone ethinyl estradiol norgestimatec ethinyl estradiol norethindroned Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir.If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol.If REYATAZ 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 REYATAZ or REYATAZ 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 immunosuppressantsTherapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ.Inhaled beta agonist:salmeterol salmeterolCoadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.Inhaled/nasal steroid:fluticasoneREYATAZ fluticasoneConcomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.REYATAZ with ritonavir fluticasoneConcomitant use of fluticasone propionate and REYATAZ 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 REYATAZ 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 atazanavirIncreased concentrations of clarithromycin may cause QTc prolongations; therefore, dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied.Opioids:buprenorphine buprenorphine norbuprenorphine Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. PDE5 inhibitors:sildenafil, tadalafil, vardenafil sildenafil tadalafil vardenafilCoadministration with REYATAZ 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 REYATAZ 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 REYATAZ: Coadministration of ADCIRCA(R) in patients on REYATAZ (with or without ritonavir): oFor patients receiving REYATAZ (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 REYATAZ (with or without ritonavir) in patients on ADCIRCA(R): oAvoid the use of ADCIRCA(R) when starting REYATAZ (with or without ritonavir). Stop ADCIRCA(R) at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (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. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.REYATAZ: 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 atazanavirPlasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 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 REYATAZ 300 mg with ritonavir 100 mg dose.In treatment-experienced adult patients:The use of PPIs in treatment-experienced patients receiving REYATAZ is not recommended.. oREYATAZ 300 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with an H2RA.. oREYATAZ 400 mg with ritonavir 100 mg once daily (all as single dose with food) if taken with both tenofovir DF and an H2RA.. oREYATAZ 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. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA.. Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. Coadministration of REYATAZ 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 REYATAZ:. Coadministration of ADCIRCA(R) in patients on REYATAZ (with or without ritonavir):. oFor patients receiving REYATAZ (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.. oFor patients receiving REYATAZ (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 REYATAZ (with or without ritonavir) in patients on ADCIRCA(R):. oAvoid the use of ADCIRCA(R) when starting REYATAZ (with or without ritonavir). Stop ADCIRCA(R) at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA(R) at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.. oAvoid the use of ADCIRCA(R) when starting REYATAZ (with or without ritonavir). Stop ADCIRCA(R) at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA(R) at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.. 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.. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.. 7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ 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)].

MICROBIOLOGY SECTION.

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 (EC50) 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 EC50 values above the EC50 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 REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 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 Failuresa at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Subjectsa 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. Mixture of I50I/L emerged in other atazanavir 400 mg-treated subjects. Neither isolate was phenotypically resistant to atazanavir.REYATAZ 300 mgwithritonavir 100 mg(n=95)REYATAZ 400 mg(n=105)Virologic Failure (>=50 copies/mL) at Week 9615 (16%)34 (32%)Virologic Failure with Genotypes and Phenotypes Data 517Virologic Failure Isolates with atazanavir-resistance at Week 960/5 (0%)b 4/17 (24%)b Virologic Failure Isolates with I50L Emergence at Week 96c 0/5 (0%)b 2/17 (12%)b Virologic Failure Isolates with Lamivudine Resistance at Week 962/5 (40%)b 11/17 (65%)b Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 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 subject 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/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 REYATAZ 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive subjects who experienced virologic failure on REYATAZ 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 1-2 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 Analysisa 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.Virologic Response HIV-1 RNA <400 copies/mLb Number and Type of Baseline PISubstitutionsa atazanavir with ritonavir(n=110)lopinavir/ritonavirc (n=113)3 or more primary PI substitutions includingd: D30N75% (6/8)50% (3/6) M36I/V19% (3/16)33% (6/18) M46I/L/T24% (4/17)23% (5/22) I54V/L/T/M/A31% (5/16)31% (5/16) A71V/T/I/G34% (10/29)39% (12/31) G73S/A/C/T14% (1/7)38% (3/8) V77I47% (7/15)44% (7/16) V82A/F/T/S/I29% (6/21)27% (7/26) I84V/A11% (1/9)33% (2/6) N88D63% (5/8)67% (4/6) L90M10% (2/21)44% (11/25)Number of baseline primary PI substitutionsa All patients, as-treated58% (64/110)59% (67/113)0-2 PI substitutions75% (50/67)75% (50/67)3-4 PI substitutions41% (14/34)43% (12/28)5 or more PI substitutions0% (0/9)28% (5/18)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 REYATAZ.Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Subjects in Study AI424-045, As-Treated AnalysisVirologic Response HIV RNA <400 copies/mLb Baseline Phenotypea atazanavir with ritonavir(n=111)lopinavir/ritonavirc (n=111)a 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. 0-271% (55/78)70% (56/80) >2-553% (8/15)44% (4/9) >5-1013% (1/8)33% (3/9) >1010% (1/10)23% (3/13).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling:ocardiac conduction abnormalities [see Warnings and Precautions (5.1)]orash [see Warnings and Precautions (5.2)]ohyperbilirubinemia [see Warnings and Precautions (5.8)]ochronic kidney disease [see Warnings and Precautions (5.5)]onephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)]. ocardiac conduction abnormalities [see Warnings and Precautions (5.1)]. orash [see Warnings and Precautions (5.2)]. ohyperbilirubinemia [see Warnings and Precautions (5.8)]. ochronic kidney disease [see Warnings and Precautions (5.5)]. onephrolithiasis 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 Bristol-Myers Squibb at 1-800-721-5072 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 REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects received REYATAZ 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 subjects receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables and 8, respectively.Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,b Study AI424-138 None reported in this treatment arm. Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on the regimen containing REYATAZ. Median time on therapy. Administered as fixed-dose As fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily.96 weeksc REYATAZ 300 mg with ritonavir 100 mg (once daily) andtenofovir DF/emtricitabined (n=441)96 weeksc lopinavir/ritonavird 400 mg/100 mg (twice daily) andtenofovir DF/emtricitabinee (n=437)Digestive System Nausea4%8% Jaundice/scleral icterus5% Diarrhea2%12%Skin and Appendages Rash3%2%Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,b Studies AI424-034, AI424-007, and AI424-008 None reported in this treatment arm. Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on regimens containing REYATAZ. Median time on therapy. Includes long-term follow-up. As fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.Study AI424-034Studies AI424-007, -00864 weeksc REYATAZ400 mg (once daily)with lamivudine/zidovudinee (n=404)64 weeksc efavirenz600 mg (once daily)with lamivudine/zidovudinee (n=401)120 weeksc,d REYATAZ400 mg (once daily)with stavudine andlamivudine ordidanosine(n=279)73 weeksc,d nelfinavir750 mg TID or1250 mg BID withstavudine andlamivudine ordidanosine(n=191)Body as Whole Headache6%6%1%2%Digestive System Nausea14%12%6%4% Jaundice/scleral icterus7%7% Vomiting4%7%3%3% Abdominal pain4%4%4%2% Diarrhea1%2%3%16%Nervous System Insomnia3%3%<1% Dizziness2%7%<1% Peripheral neurologic symptoms<1%1%4%3%Skin and Appendages Rash7%10%5%1%. Adverse Reactions in Treatment-Experienced Adult Subjects The safety profile of REYATAZ 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 subjects receiving REYATAZ with ritonavir are presented in Table 9.Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in >=2% of Adult Treatment-Experienced Subjects with HIV-1 Infection,b Study AI424-045 None reported in this treatment arm. Includes events of possible, probable, certain, or unknown relationship to treatment regimen. Based on the regimen containing REYATAZ. Median time on therapy. As fixed-dose product.48 weeksc REYATAZ with ritonavir 300/100 mg(once daily) and tenofovir DF and NRTI(n=119)48 weeksc lopinavir/ritonavir 400/100 mg(twice dailyd) and tenofovir DF and NRTI(n=118)Body as Whole Fever2%Digestive System Jaundice/scleral icterus9% Diarrhea3%11% Nausea3%2%Nervous System Depression2%<1%Musculoskeletal System Myalgia4%. Laboratory Abnormalities in Treatment-Naive Subjects The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3-4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.Table 10: Grade 3-4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,a Study AI424-138a Based on the regimen containing REYATAZ. Median time on therapy. Administered as fixed-dose product As fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. ULN=upper limit of normal.96 weeksb REYATAZ 300 mgwith ritonavir 100 mg(once daily) and tenofovir DF/emtricitabinec 96 weeksb lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined VariableLimite (n=441)(n=437)ChemistryHigh SGOT/AST>=5.1 ULN3%1% SGPT/ALT>=5.1 ULN3%2% Total Bilirubin>=2.6 ULN44%<1% Lipase>=2.1 ULN2%2% Creatine Kinase>=5.1 ULN8%7% Total Cholesterol>=240 mg/dL11%25%HematologyLow Neutrophils<750 cells/mm3 5%2%Table 11: Grade 3-4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Subjects with HIV-1 Infection,a Studies AI424-034, AI424-007, and AI424-008 None reported in this treatment arm. Based on regimen(s) containing REYATAZ. 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.Study AI424-034Studies AI424-007, -00864 weeksb REYATAZ400 mgonce dailyand lamivudine/zidovudinee 64 weeksb efavirenz600 mgonce dailyand lamivudine/zidovudinee 120 weeksb,c REYATAZ400 mgonce dailywith stavudineand lamivudine orwith stavudineand didanosine73 weeksb,c nelfinavir750 mg TID or1250 mg BIDwith stavudineand lamivudine orwith stavudineand didanosineVariableLimitd (n=404)(n=401)(n=279)(n=191)ChemistryHigh SGOT/AST>=5.1 ULN2%2%7%5% SGPT/ALT>=5.1 ULN4%3%9%7% Total Bilirubin>=2.6 ULN35%<1%47%3% Amylase>=2.1 ULN14%10% Lipase>=2.1 ULN<1%1%4%5% Creatine Kinase>=5.1 ULN6%6%11%9% Total Cholesterol>=240 mg/dL6%24%19%48% Triglycerides>=751 mg/dL<1%3%4%2%HematologyLow Hemoglobin<8.0 g/dL5%3%<1%4% Neutrophils<750 cells/mm3 7%9%3%7%. Total Bilirubin. 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 AI424-138a REYATAZ 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 REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ 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 subjects with LDL-cholesterol measured. Fasting.REYATAZ with ritonavira,b lopinavir/ritonavirb,c BaselineWeek 48Week 96BaselineWeek 48Week 96mg/dLmg/dLChanged mg/dLChanged mg/dLmg/dLChanged mg/dLChanged (n=428e)(n=372e)(n=372e)(n=342e)(n=342e)(n=424e)(n=335e)(n=335e)(n=291e)(n=291e)LDL-Cholesterolf 92105+14%105+14%93111+19%110+17%HDL-Cholesterolf 3746+29%44+21%3648+37%46+29%Total Cholesterolf 149169+13%169+13%150187+25%186+25%Triglyceridesf 126145+15%140+13%129194+52%184+50%Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034a REYATAZ 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 REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ 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.REYATAZa,b efavirenzb,c Baselinemg/dL(n=383e)Week 48mg/dL(n=283e)Week 48Changed (n=272e)Baselinemg/dL(n=378e)Week 48mg/dL(n=264e)Week 48Changed (n=253e)LDL-Cholesterolf 9898+1%98114+18%HDL-Cholesterol3943+13%3846+24%Total Cholesterol164168+2%162195+21%Triglyceridesf 138124-9%129168+23%. 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 REYATAZ with ritonavir having Grade 3-4 laboratory abnormalities, are presented in Table 14.Table 14: Grade 3-4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045a Based on regimen(s) containing REYATAZ. Median time on therapy. ULN upper limit of normal. As fixed-dose product.48 weeksb 48 weeksb REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTIlopinavir/ritonavir400/100 mg (twice dailyd) and tenofovir DF and NRTIVariableLimitc (n=119)(n=118)ChemistryHigh SGOT/AST>=5.1 ULN3%3% SGPT/ALT>=5.1 ULN4%3% Total Bilirubin>=2.6 ULN49%<1% Lipase>=2.1 ULN5%6% Creatine Kinase>=5.1 ULN8%8% Total Cholesterol>=240 mg/dL25%26% Triglycerides>=751 mg/dL8%12% Glucose>=251 mg/dL5%<1%HematologyLow Platelets<50,000 cells/mm3 2%3% Neutrophils<750 cells/mm3 7%8%. 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 REYATAZ 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 AI424-045a REYATAZ 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 REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ 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 subjects 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.REYATAZ with ritonavira,b Lopinavir/ritonavirb,c Baselinemg/dL(n=111e)Week 48mg/dL(n=75e)Week 48Changed (n=74e)Baselinemg/dL(n=108e)Week 48mg/dL(n=76e)Week 48Changed (n=73e)LDL-Cholesterolf 10898-10%104103+1%HDL-Cholesterol4039-7%3941+2%Total Cholesterol188170-8%181187+6%Triglyceridesf 215161-4%196224+30%. Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Capsules The safety and tolerability of REYATAZ 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 REYATAZ 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 REYATAZ in adults. The most common Grade 2-4 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 3-4 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 3-4 laboratory abnormalities occurred with frequency of less than 3%.. Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least kg to less than 35 kg, including 134 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from months to 10 years of age. In these studies, 51% were female and 49% were male. All subjects received ritonavir and nucleoside reverse transcriptase inhibitors (NRTIs).The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3-4 laboratory abnormalities occurring in pediatric subjects weighing kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (>=2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3-4 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 REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.In Study AI424-045, 20 subjects administered REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 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 REYATAZ, 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 REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ 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 REYATAZ. 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: edemaCardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)] Gastrointestinal System: pancreatitisHepatic 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: arthralgiaRenal 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility . Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.. Mutagenesis Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).. Impairment of Fertility At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES . 14.1 Adult Subjects without Prior Antiretroviral Therapy Study AI424-138: 96-week study comparing the antiviral efficacy and safety of either REYATAZ 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 REYATAZ (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: 19-72), 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/mm3 (range: to 810 cells/mm3) 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)a 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.REYATAZ300 mg with ritonavir 100 mg(once daily) andtenofovir DF/emtricitabine(once daily)a (n=441)lopinavir/ritonavirb 400 mg/100 mg(twice daily) withtenofovir DF/emtricitabine(once daily)a (n=437)Outcome96 Weeks96 WeeksResponderc,d,e 75%68%Virologic failuref 17%19% Rebound8%10% Never suppressed through Week 969%9%Death1%1%Discontinued due to adverse event3%5%Discontinued for other reasonsg 4%7%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 REYATAZ 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 REYATAZ with ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm.Study AI424-034: REYATAZ 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 REYATAZ (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/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 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)a 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. As fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.OutcomeREYATAZ400 mg once dailyand lamivudine/zidovudined (n=405)efavirenz600 mg once dailyand lamivudine/zidovudined (n=405)Respondera 67% (32%)62% (37%)Virologic failureb 20%21% Rebound17%16% Never suppressed through Week 483%5%Death-<1%Discontinued due to adverse event5%7%Discontinued for other reasonsc 8%10%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 REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm. Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 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 REYATAZ, comparing REYATAZ 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/mm3 (range: to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 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)a 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.OutcomeREYATAZ400 mg once daily withlamivudine and stavudine(n=181)nelfinavir1250 mg twice daily withlamivudine and stavudine(n=91)Respondera 67% (33%)59% (38%)Virologic failureb 24%27% Rebound14%14% Never suppressed through Week 4810%13%Death<1%-Discontinued due to adverse event1%3%Discontinued for other reasonsc 7%10%Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.. 14.2 Adult Subjects with Prior Antiretroviral Therapy Study AI424-045: REYATAZ once daily with ritonavir once daily compared to REYATAZ 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 REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (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/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).Treatment outcomes through Week 48 for the REYATAZ with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach definitive conclusion that REYATAZ 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)a Time-averaged difference through Week 48 for HIV-1 RNA; Week 48 difference in HIV-1 RNA percentages and CD4+ mean changes, REYATAZ 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(TM) Assay, test version 1.5. Protocol-defined primary efficacy outcome measure. Based on subjects with baseline and Week 48 CD4+ cell count measurements (REYATAZ 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.OutcomeREYATAZ 300 mg with ritonavir 100 mg once daily and tenofovir DF and NRTI (n=119) lopinavir/ritonavir(400/100 mg) twice dailyand tenofovir DF and NRTI (n=118)Differencea (REYATAZ-lopinavir/ritonavir)b (CI)HIV-1 RNA Change from Baseline (log10 copies/mL)c -1.58-1.70+0.12c (-0.17, 0.41)CD4+ Change from Baseline (cells/mm3)e 116123-7(-67, 52)Percent of Subjects Respondinge HIV-1 RNA <400 copies/mLc 55%57%-2.2%(-14.8%, 10.5%) HIV-1 RNA <50 copies/mLc 38%45%-7.1%(-19.6%, 5.4%)No subjects in the REYATAZ 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 REYATAZ 400 mg with saquinavir (n=115) was -1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of subjects in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ 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 REYATAZ (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 REYATAZ (n=144) and 69% (53%) for subjects randomized to lopinavir/ritonavir (n=146). The mean change from baseline was -1.59 log10 copies/mL in the REYATAZ treatment arm and -2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI-experienced subjects with prior virologic failure and is not recommended for such patients.. 14.3 Pediatric Subjects . Pediatric Trials with REYATAZ Capsules Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ 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 REYATAZ 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 REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and experienced subjects with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive subjects and 220 cells/mm3 in antiretroviral-experienced subjects.. Pediatric Trials with REYATAZ Oral Powder Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.oAI424-397 (PRINCE I; NCT01099579): In pediatric subjects from months to less than years of ageoAI424-451 (PRINCE II; NCT01335698): In pediatric subjects from months to less than 11 years of ageIn these studies 155 subjects (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder with ritonavir, in combination with two NRTIs.For inclusion in both trials, treatment-naive subjects had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced subjects had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least NRTIs. Subjects exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Subjects who received REYATAZ or REYATAZ with ritonavir at any time prior to study enrollment or who had history of treatment failure on two or more protease inhibitors were excluded from the trials.One hundred thirty-four (134) subjects from both studies weighing kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated. Subjects kg to less than 10 kg received either 150 mg or 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution; and subjects 25 kg to less than 35 kg received 300 mg REYATAZ and 100 mg ritonavir.Using modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced subjects with HIV-1 RNA <400 copies/mL at Week 48 were 79% (41/52) and 62% (51/82), respectively in subjects who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced subjects with HIV-1 RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively, in subjects who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy (last observation carried forward) was 215 cells/mm3 (6%) in antiretroviral-naive subjects and 133 cells/mm3 (4%) in antiretroviral-experienced subjects who received REYATAZ oral powder with ritonavir.. oAI424-397 (PRINCE I; NCT01099579): In pediatric subjects from months to less than years of age. oAI424-451 (PRINCE II; NCT01335698): In pediatric subjects from months to less than 11 years of age.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE REYATAZ(R) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients months and older weighing at least kg.Limitations of Use:oREYATAZ is not recommended for use in pediatric patients below the age of months due to the risk of kernicterus [see Use in Specific Populations (8.4)].oUse of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)].. oREYATAZ is not recommended for use in pediatric patients below the age of months due to the risk of kernicterus [see Use in Specific Populations (8.4)].. oUse of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)].. REYATAZ is protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients months and older weighing at least kg. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use ).REYATAZ is not cure for HIV-1 infection. Advise patients to remain under the care of healthcare provider while using REYATAZ.. Cardiac Conduction Abnormalities Inform patients that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Tell patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)].. Severe Skin Reaction Inform patients that there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue REYATAZ and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].. Hyperbilirubinemia Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8) ].. Patients with Phenylketonuria Advise caregivers of patients with phenylketonuria that REYATAZ oral powder contains phenylalanine [see Warnings and Precautions (5.3) ].. Chronic Kidney Disease Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ [see Warnings and Precautions (5.5)].. Nephrolithiasis and Cholelithiasis Inform patients that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6)].. Drug Interactions REYATAZ may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. Johns wort, to their healthcare provider prior to use [see Contraindications (4), Warnings and Precautions (5.7)].Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.10) ].. Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11) ].. Dosing Instructions Advise patients to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if dose of REYATAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if dose is skipped the patient should not double the next dose.. Pregnancy Inform pregnant patients that there is pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)].LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. REYATAZ can also be passed to the baby in breast milk and it is not known whether it could harm the baby [see Use in Specific Populations (8.2)].

INSTRUCTIONS FOR USE SECTION.

Instructions for Use Instructions for UseREYATAZ(R) (RAY-ah-taz)(atazanavir)oral powderRead this Instructions for Use before you prepare your childs first dose of REYATAZ oral powder, each time you get refill, and as needed. There may be new information. This information does not take the place of talking to your childs healthcare provider about their medical condition or treatment. Ask your childs healthcare provider or pharmacist if you have questions about how to mix or give dose of REYATAZ oral powder.Important information:oFor more information about REYATAZ oral powder, see the Patient Information leaflet.oREYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.oREYATAZ oral powder must be taken with ritonavir.oTalk with your childs healthcare provider to help decide the best schedule for giving your child REYATAZ oral powder.Instructions for mixing REYATAZ oral powder:REYATAZ oral powder should be mixed with food such as applesauce or yogurt, instead of liquid (milk, infant formula, or water) in young children and infants who can take food.oInfants less than months old and who cannot eat solid food or drink from cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe.oREYATAZ oral powder that is mixed in infant formula or liquid should not be given using baby bottle.When preparing REYATAZ oral powder with either food or liquid, choose clean, flat work surface. Place clean paper towel on the work surface. Place the supplies you will need on the paper towel.Wash and dry your hands before and after preparing REYATAZ oral powder.Preparing dose of REYATAZ oral powder mixed with food:Before you prepare dose of REYATAZ oral powder mixed with food, gather the following supplies:opaper towelotablespoonosmall clean container (such as small cup or bowl) oa food such as applesauce or yogurtothe correct number of packets of REYATAZ oral powder needed for the prescribed doseoa clean pair of scissorsStep 1. Place at least tablespoon of food such as applesauce or yogurt in the small container (see Figure A).Figure AStep 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure B).Figure BStep 3. Using clean pair of scissors, cut open the packet on the dotted line (see Figure C).Figure CStep 4. Empty the contents of the packet into the small container onto the food (see Figure D).Figure DRepeat Steps through for each packet of REYATAZ oral powder needed for the total prescribed dose.Step 5. Use tablespoon to gently mix the powder and the food together (see Figure E).Figure ESteps through must be completed within hour of mixing the medicine.Step 6. Use the tablespoon or small spoon to feed the REYATAZ oral powder and food mixture to your child. Look in your childs mouth to make sure that all of the mixture is swallowed.Step 7. Add tablespoon more of food to the empty container and gently stir to mix with any contents that may still be in the container.Step 8. Use the tablespoon or small spoon to feed your child the mixture, making sure your child has swallowed all of the mixture.Step 9. Give your child ritonavir as prescribed right after taking REYATAZ oral powder.Step 10. Wash the container and tablespoon. Allow the container and spoon to dry. Throw away the paper towel and clean the work surface.Preparing dose of REYATAZ oral powder mixed with liquid in small drinking cup:Before you prepare dose of REYATAZ oral powder mixed with liquid in small drinking cup, gather the following supplies:opaper towelospoono30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F.osmall drinking cupoliquid such as milk or waterothe correct number of packets of REYATAZ oral powder needed for the prescribed doseoa clean pair of scissorsFigure FStep 1. Using the 30 mL medicine cup, pour at least 30 mL of liquid into the small drinking cup (see Figure G).Figure GStep 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure H).Figure HStep 3. Using clean pair of scissors, cut open the packet on the dotted line (see Figure I).Figure IStep 4. Empty the contents of the packet into the small drinking cup (see Figure J).Figure JRepeat Steps through for each packet of REYATAZ oral powder needed for the total prescribed dose.Step 5. Hold the small drinking cup with one hand. With your other hand, use the spoon to gently mix the powder and the liquid (see Figure K).Figure KSteps and must be completed within hour of mixing the medicine.Step 6. Have your child drink all of the mixture in the small drinking cup.Step 7. To make sure there is no mixture left in the small drinking cup add 15 mL more liquid to the small drinking cup:oStir with the spoon.oRepeat Step above.If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.Step 8. Give your child ritonavir as prescribed right after taking REYATAZ oral powder.Step 9. Wash the small drinking cup, medicine cup, and spoon. Allow the small drinking cup, medicine cup, and spoon to dry. Throw away the paper towel and clean the work surface.Preparing dose of REYATAZ oral powder mixed with liquid infant formula using an oral dosing syringe and small medicine cup:Before you prepare dose of REYATAZ oral powder mixed with infant formula using an oral dosing syringe, gather the following supplies:opaper towelosmall spoono30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure L.o10 mL oral dosing syringe (ask your pharmacist for this). See Figure L.oinfant formulaothe correct number of packets of REYATAZ oral powder needed for the prescribed doseoa clean pair of scissorsFigure LStep 1. Prepare the infant formula according to the directions on the infant formula package.Step 2. Pour 10 mL of infant formula into the medicine cup (see Figure M).Figure MStep 3. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure N).Figure NStep 4. Using clean pair of scissors, cut open the packet on the dotted line (see Figure O).Figure OStep 5. Empty the contents of the packet into the medicine cup (see Figure P).Figure PRepeat Steps through for each packet of REYATAZ oral powder needed for the total prescribed dose.Step 6. Hold the medicine cup with one hand. With your other hand, use the small spoon to gently mix the powder and the infant formula (see Figure Q).Figure QSteps through must be completed within hour of mixing the medicine.Step 7. Draw up the powder and infant formula mixture into the oral dosing syringe as follows:oCheck that the plunger is completely pushed into barrel of the syringe (see Figure R).Figure RoPlace the tip of the syringe into the powder and infant formula mixture in the medicine cup (see Figure S).Figure SoSlowly pull back on the plunger and draw up 10 mL of the mixture (see Figure T).Figure TStep 8. Place the tip of the oral dosing syringe in your babys mouth along the inner cheek on either the right or left side (see Figure U). Slowly push on the plunger to give your baby all of the REYATAZ oral powder and infant formula mixture.oDraw up any remaining mixture with the oral dosing syringe and repeat until all of the mixture has been given to the baby.Figure UStep 9. To make sure there is no mixture left in the medicine cup or syringe:oRepeat Step above to add 10 mL more infant formula to the medicine cup.oStir with small spoon.oThen repeat Steps through above.To make sure that your baby gets all of the medicine, do not give REYATAZ oral powder in baby bottle.Step 10. Give your baby ritonavir as prescribed right after taking REYATAZ oral powder.Step 11. Remove the plunger from the oral dosing syringe. Wash the medicine cup, spoon, and oral dosing syringe. Allow the medicine cup, spoon, and oral dosing syringe to dry. Throw away the paper towel and clean the work surface.How should store REYATAZ oral powderoStore REYATAZ oral powder at temperature of 68F to 86F (20C to 30C).oStore REYATAZ oral powder in the original packet. Do not open until ready to use.oAfter REYATAZ oral powder is mixed with food or liquid, it may be kept at temperature of 68F to 86F (20C to 30C) for up to hour. Take REYATAZ oral powder within hour after mixing with food or liquid. Keep REYATAZ oral powder and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Distributed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543 USA[print code]Revised: September 2020. oFor more information about REYATAZ oral powder, see the Patient Information leaflet.. oREYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.. oREYATAZ oral powder must be taken with ritonavir.. oTalk with your childs healthcare provider to help decide the best schedule for giving your child REYATAZ oral powder.. oInfants less than months old and who cannot eat solid food or drink from cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe.. oREYATAZ oral powder that is mixed in infant formula or liquid should not be given using baby bottle.. opaper towel. otablespoon. osmall clean container (such as small cup or bowl) oa food such as applesauce or yogurt. othe correct number of packets of REYATAZ oral powder needed for the prescribed dose. oa clean pair of scissors. opaper towel. ospoon. o30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F.. osmall drinking cup. oliquid such as milk or water. othe correct number of packets of REYATAZ oral powder needed for the prescribed dose. oa clean pair of scissors. oStir with the spoon.. oRepeat Step above.. opaper towel. osmall spoon. o30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure L.. o10 mL oral dosing syringe (ask your pharmacist for this). See Figure L.. oinfant formula. othe correct number of packets of REYATAZ oral powder needed for the prescribed dose. oa clean pair of scissors. oCheck that the plunger is completely pushed into barrel of the syringe (see Figure R).. oPlace the tip of the syringe into the powder and infant formula mixture in the medicine cup (see Figure S).. oSlowly pull back on the plunger and draw up 10 mL of the mixture (see Figure T).. oDraw up any remaining mixture with the oral dosing syringe and repeat until all of the mixture has been given to the baby.. oRepeat Step above to add 10 mL more infant formula to the medicine cup.. oStir with small spoon.. oThen repeat Steps through above.. oStore REYATAZ oral powder at temperature of 68F to 86F (20C to 30C).. oStore REYATAZ oral powder in the original packet. Do not open until ready to use.. oAfter REYATAZ oral powder is mixed with food or liquid, it may be kept at temperature of 68F to 86F (20C to 30C) for up to hour. Take REYATAZ oral powder within hour after mixing with food or liquid.. Keep REYATAZ oral powder and all medicines out of the reach of children.. This Instructions for Use has been approved by the U.S. Food and Drug Administration.. Reyataz Figure A. Reyataz Figure B. Reyataz Figure C. Reyataz Figure D. Reyataz Figure E. Reyataz Figure F. Reyataz Figure G. Reyataz Figure H. Reyataz Figure I. Reyataz Figure J. Reyataz Figure K. Reyataz Figure L. Reyataz Figure M. Reyataz Figure N. Reyataz Figure O. Reyataz Figure P. Reyataz Figure Q. Reyataz Figure R. Reyataz Figure S. Reyataz Figure T. Reyataz Figure U.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS REYATAZ is contraindicated:oin patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2)].owhen coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).owhen coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).Table displays drugs that are contraindicated with REYATAZ.Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA(R) for erectile dysfunction.Drug ClassDrugs within class that are contraindicated with REYATAZAlpha 1-adrenoreceptor antagonistAlfuzosinAntiarrhythmicsAmiodarone (with ritonavir), quinidine (with ritonavir)Antimycobacterials RifampinAntineoplastics IrinotecanAntipsychoticsLurasidone (with ritonavir), pimozideBenzodiazepinesTriazolam, orally administered midazolama Ergot DerivativesDihydroergotamine, ergotamine, ergonovine, methylergonovineGI Motility AgentCisaprideHepatitis Direct-Acting AntiviralsElbasvir/grazoprevir; glecaprevir/pibrentasvirHerbal ProductsSt. Johns wort (Hypericum perforatum)Lipid-Modifying Agents:Lovastatin, simvastatin, lomitapidePhosphodiesterase-5 (PDE-5) InhibitorSildenafilb when dosed as REVATIO(R) for the treatment of pulmonary arterial hypertension Protease InhibitorsIndinavirNon-nucleoside Reverse Transcriptase InhibitorsNevirapine. oin patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2)].. owhen coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).. owhen coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).. oREYATAZ is contraindicated in patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)oCoadministration with alfuzosin, amiodarone (if REYATAZ is coadministered with ritonavir), quinidine (if REYATAZ is coadministered with ritonavir), triazolam, orally administered midazolam, ergot derivatives, rifampin, irinotecan, lurasidone (if REYATAZ is coadministered with ritonavir), lovastatin, simvastatin, lomitapide, indinavir, cisapride, pimozide, St. Johns wort, nevirapine, elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sildenafil when dosed as REVATIO(R). (4) oREYATAZ is contraindicated in patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4). oCoadministration with alfuzosin, amiodarone (if REYATAZ is coadministered with ritonavir), quinidine (if REYATAZ is coadministered with ritonavir), triazolam, orally administered midazolam, ergot derivatives, rifampin, irinotecan, lurasidone (if REYATAZ is coadministered with ritonavir), lovastatin, simvastatin, lomitapide, indinavir, cisapride, pimozide, St. Johns wort, nevirapine, elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sildenafil when dosed as REVATIO(R). (4).

DESCRIPTION SECTION.

11 DESCRIPTION The active ingredient in REYATAZ capsules and oral powder is atazanavir sulfate, which is an HIV-1 protease inhibitor.The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7oH2SO4, which corresponds to molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:Atazanavir sulfate is white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of saturated solution in water being about 1.9 at 24 +- 3C.REYATAZ Capsules are available for oral administration in strengths of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.REYATAZ oral powder comes in packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor.. Reyataz Chemic Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . oPretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2) oTreatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3) oTreatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3) oPediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4) oREYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than kg. (2.5) oPregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6) oDosing modifications: may be required for concomitant therapy 2.3, 2.4, 2.5, 2.6), renal impairment (2.7), and hepatic impairment (2.8).. oPretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2) oTreatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3) oTreatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3) oPediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4) oREYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than kg. (2.5) oPregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6) oDosing modifications: may be required for concomitant therapy 2.3, 2.4, 2.5, 2.6), renal impairment (2.7), and hepatic impairment (2.8).. 2.1 Overview oREYATAZ capsules and oral powder must be taken with food.oDo not open the capsules.oThe recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)].oREYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)].oREYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than kg [see Dosage and Administration (2.5)].oEfficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.. oREYATAZ capsules and oral powder must be taken with food.. oDo not open the capsules.. oThe recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)].. oREYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)].. oREYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than kg [see Dosage and Administration (2.5)].. oEfficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.. 2.2 Testing Prior to Initiation and During Treatment with REYATAZ Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6)].Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see Warnings and Precautions (5.4)].. 2.3 Dosage of REYATAZ in Adult Patients Table displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.Table 1: Recommended REYATAZ and Ritonavir Dosage in Adultsa,b See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.REYATAZ Once DailyDosageRitonavir Once DailyDosageTreatment-Naive Adult Patients recommended regimen300 mg100 mg unable to tolerate ritonavir400 mgN/A in combination with efavirenz400 mg100 mgTreatment-Experienced Adult Patients recommended regimen300 mg100 mg in combination with both H2RA and tenofovir DF400 mg100 mg. 2.4 Dosage of REYATAZ Capsules in Pediatric Patients The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)a,b Administer REYATAZ capsules and ritonavir simultaneously with food. The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.Body weightREYATAZ Daily DosageRitonavir Daily DosageTreatment-Naive and Treatment-Experiencedc Less than 15 kgCapsules not recommendedN/AAt least 15 kg to less than 35 kg200 mg100 mgAt least 35 kg300 mg100 mgTreatment-Naive, at least 13 years old and cannot tolerate ritonavirAt least 40 kg400 mgN/AWhen transitioning between formulations, change in dose may be needed. Consult the dosing table for the specific formulation.. 2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least months of age and weighing at least kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table displays the recommended dosage of REYATAZ oral powder and ritonavir.Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least months of age and weighing at least kg)a,b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. Only patients weighing to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. Each packet contains 50 mg of REYATAZ.Body WeightDaily Dosage of REYATAZOral PowderDaily Dosage of RitonavirOral Solution5 kg to less than 15 kg200 mg (4 packets)c,d 80 mg15 kg to less than 25 kg250 mg (5 packets)d 80 mgWhen transitioning between formulations, change in dose may be needed. Consult the dosing table for the specific formulation.. Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use] oDetermine the number of packets (3, 4, or packets) that are needed.oPrior to mixing, tap the packet to settle the powder.oIt is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with beverage (milk, infant formula, or water) may be used for infants who can drink from cup. For young infants (less than months) who cannot eat solid food or drink from cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.oUse clean pair of scissors to cut each packet along the dotted line.oMixing with food: Using spoon, mix the recommended number of REYATAZ oral powder packets with minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.oMixing with beverage such as milk or water in small drinking cup: Using spoon, mix the recommended number of REYATAZ oral powder packets with minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.oMixing with liquid infant formula using an oral dosing syringe and small medicine cup: Using spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.oAdminister ritonavir immediately following REYATAZ powder administration.oAdminister the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at temperature of 68F to 86F (20C to 30C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.. oDetermine the number of packets (3, 4, or packets) that are needed.. oPrior to mixing, tap the packet to settle the powder.. oIt is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with beverage (milk, infant formula, or water) may be used for infants who can drink from cup. For young infants (less than months) who cannot eat solid food or drink from cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.. oUse clean pair of scissors to cut each packet along the dotted line.. oMixing with food: Using spoon, mix the recommended number of REYATAZ oral powder packets with minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.. oMixing with beverage such as milk or water in small drinking cup: Using spoon, mix the recommended number of REYATAZ oral powder packets with minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.. oMixing with liquid infant formula using an oral dosing syringe and small medicine cup: Using spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.. oAdminister ritonavir immediately following REYATAZ powder administration.. oAdminister the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at temperature of 68F to 86F (20C to 30C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.. 2.6 Dosage Adjustments in Pregnant Patients Table includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1)].Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patientsa See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA.REYATAZOnce DailyDosageRitonavirOnce DailyDosageTreatment-Naive and Treatment-ExperiencedRecommended Regimen300 mg100 mgTreatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DFb In combination with EITHER H2RA OR tenofovir DF400 mg100 mg. 2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7)].. 2.8 Dosage Adjustments in Patients with Hepatic Impairment Table displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic ImpairmentREYATAZ Once Daily DosageMild hepatic impairment (Child-Pugh Class A)400 mgModerate hepatic impairment (Child-Pugh Class B)300 mgSevere hepatic impairment (Child-Pugh Class C)REYATAZ with or without ritonavir is not recommended.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS REYATAZ Capsules:o150 mg capsule with blue cap and powder blue body, printed with white ink BMS 150 mg on the cap and with blue ink 3624 on the body.o200 mg capsule with blue cap and blue body, printed with white ink BMS 200 mg on the cap and with white ink 3631 on the body.o300 mg capsule with red cap and blue body, printed with white ink BMS 300 mg on the cap and with white ink 3622 on the body.REYATAZ Oral Powder:o50 mg of atazanavir as an oral powder in packet.. o150 mg capsule with blue cap and powder blue body, printed with white ink BMS 150 mg on the cap and with blue ink 3624 on the body.. o200 mg capsule with blue cap and blue body, printed with white ink BMS 200 mg on the cap and with white ink 3631 on the body.. o300 mg capsule with red cap and blue body, printed with white ink BMS 300 mg on the cap and with white ink 3622 on the body.. o50 mg of atazanavir as an oral powder in packet.. oCapsules: 150 mg, 200 mg, 300 mg. (3, 16)oOral powder: 50 mg packet. (3, 16). oCapsules: 150 mg, 200 mg, 300 mg. (3, 16). oOral powder: 50 mg packet. (3, 16).

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of REYATAZ 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 Cmax and AUC, dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING . . REYATAZ Capsules REYATAZ(R) (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures. 150 mg atazanavir equivalent to 170.8 mg atazanavir sulfate. 200 mg atazanavir equivalent to 227.8 mg atazanavir sulfate. 300 mg atazanavir equivalent to 341.69 mg atazanavir sulfate.Product StrengthCapsule Shell Color (cap/body)Markings on Capsule(ink color)Capsules per BottleNDC Numbercapbody150 mgblue/powder blueBMS 150 mg (white)3624 (blue)600003-3624-12200 mgblue/blueBMS 200 mg (white)3631(white)600003-3631-12300 mgred/blueBMS 300 mg(white)3622(white)300003-3622-12Keep capsules in tightly closed container.Store REYATAZ capsules at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. REYATAZ Oral Powder REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See Dosage and Administration (2.5) ]. Store REYATAZ oral powder at temperature of 68F to 86F (20C to 30C). Store REYATAZ oral powder in the original packet. Do not open until ready to use. After REYATAZ oral powder is mixed with food or liquid, it may be kept at temperature 68F to 86F (20C to 30C) for up to hour. Take REYATAZ oral powder within hour after mixing with food or liquid.

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY . 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility . Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.. Mutagenesis Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).. Impairment of Fertility At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

OVERDOSAGE SECTION.

10 OVERDOSAGE Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy subjects without symptomatic untoward effects. single self-administered overdose of 29.2 of REYATAZ in patient with HIV-1 infection (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)]. Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patients clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

REYATAZ 150 mg Capsules Representative Packaging See HOW SUPPLIED section for complete list of available packages of REYATAZ.NDC 0003-3624-12Bristol Myers Squibb60 Capsules REYATAZ(R) (atazanavir) capsules150 mgRx onlyNote to pharmacist: Do not cover ALERT box with pharmacy label.ALERT: Find out about medicines that should NOT be taken with REYATAZ(R) Reyataz 150 mg bottle label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, months of age and older weighing at least kg. REYATAZ 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 REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)].The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least months of age and older weighing at least kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [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 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.

PHARMACODYNAMICS SECTION.

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)].

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 REYATAZ 400 mg once daily and after administration of REYATAZ 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 Statea n=26. n=12.400 mg once daily300 mg with ritonavir100 mg once dailyParameterHealthySubjects(n=14)Subjects with HIV-1 Infection(n=13)HealthySubjects(n=28)Subjects with HIV-1 Infection(n=10)Cmax (ng/mL) Geometric mean (CV%)5199 (26)2298 (71)6129 (31)4422 (58) Mean (SD)5358 (1371)3152 (2231)6450 (2031)5233 (3033)Tmax (h) Median2.52.02.73.0AUC (ngoh/mL) Geometric mean (CV%)28132 (28)14874 (91)57039 (37)46073 (66) 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)a 8.6 (2.3)Cmin (ng/mL) Geometric mean (CV%)159 (88)120 (109)1227 (53)636 (97) Mean (SD)218 (191)273 (298)b 1441 (757)862 (838)Figure displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with light meal and after REYATAZ 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 Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax 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 REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of single 400-mg dose of REYATAZ with light meal (357 kcal, 8.2 fat, 10.6 protein) resulted in 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of single 400-mg dose of REYATAZ with high-fat meal (721 kcal, 37.3 fat, 29.4 protein) resulted in mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.Coadministration of single 300-mg dose of REYATAZ 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 Cmax 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 Cmax 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 Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either light or high-fat meal decreased the coefficient of variation of AUC and Cmax 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 REYATAZ 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. REYATAZ 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 Cmax was 9% lower, AUC was 19% higher, and Cmin 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 Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ 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 REYATAZ 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-) 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. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ 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 powder formulation are summarized in Table 18 by weight ranges [see Dosage and Administration (2.5) ].Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Subjects with HIV-1Body Weight(range in kg) [n]atazanavir with ritonavirDose (mg)Cmax ng/mLGeometric Mean(CV%)AUC ngoh/mLGeometric Mean(CV%)Cmin ng/mLGeometric Mean(CV%)5 to <10 [20]150/804131 (55%)32503 (61%)336 (76%)5 to <10 [10]200/804466 (59%)39519 (54%)550 (60%)10 to <15 [18]200/805197 (53%)50305 (67%)572 (111%)15 to <25 [32]250/805394 (46%)55687 (45%)686 (68%)25 to <35 [8]300/1004209 (52%)44329 (63%)468 (104%)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 InfectionBody Weight(range in kg)atazanavir with ritonavirDose (mg)Cmax ng/mLGeometric Mean(CV%)AUC ngoh/mLGeometric Mean(CV%)Cmin ng/mLGeometric Mean(CV%)15 to <35200/1003303 (86%)37235 (84%)538 (99%)>=35300/1002980 (82%)37643 (83%)653 (89%). Pregnancy The pharmacokinetic data from pregnant women with HIV-1 infection receiving REYATAZ 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 Statea 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 (4-12 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. Cmin is concentration 24 hours post-dose.Atazanavir 300 mg with ritonavir 100 mgPharmacokinetic Parameter2nd Trimester(n=5a)3rd Trimester(n=20)Postpartumb (n=34)Cmax ng/mL Geometric mean (CV%)3078.85(50)3291.46(48)5721.21(31)AUC ngoh/mL Geometric mean (CV%)27657.1(43)34251.5(43)61990.4(32)Cmin ng/mLc Geometric mean (CV%)538.70(46)668.48(50)1462.59(45). Drug Interaction Data Atazanavir is metabolism-dependent CYP3A inhibitor, with Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 uM. Atazanavir is also direct inhibitor for UGT1A1 (Ki=1.9 uM) and CYP2C8 (Ki=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, REYATAZ 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 REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin 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). REYATAZ did not have significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugsa CoadministeredDrugCoadministered DrugDose/ScheduleREYATAZDose/ScheduleRatio (90% Confidence Interval) of AtazanavirPharmacokinetic Parameters with/withoutCoadministered Drug;No Effect 1.00Cmax AUCCmin Data provided are under fed conditions unless otherwise noted. All drugs were given under fasted conditions. REYATAZ 300 mg with ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean Cmax that was similar and AUC and Cmin values that were 1.79- and 4.46-fold higher relative to REYATAZ 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 with 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 Cmax, AUC, and Cmin 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 REYATAZ. Omeprazole 20 mg was administered 30 minutes prior to light meal in the morning and REYATAZ 300 mg with ritonavir 100 mg in the evening after light meal, separated by 12 hours from omeprazole. REYATAZ 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 Cmin (2.4-fold), with decrease in Cmax (29%) relative to REYATAZ 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 REYATAZ 400 mg with ritonavir 100 mg once daily after light meal, hour after omeprazole. Effects on atazanavir concentrations were similar when REYATAZ 400 mg with ritonavir 100 mg was separated from omeprazole 20 mg by 12 hours. REYATAZ 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 Cmin (3.3-fold), with decrease in Cmax (26%) relative to REYATAZ 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 Cmax, AUC, and Cmin by 18%, 103%, and 671%, respectively. Note that similar results were observed in studies where administration of tenofovir DF and REYATAZ was separated by 12 hours. Ratio of atazanavir with ritonavir and tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir exposure than atazanavir 400 mg (see footnote o). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered with ritonavir and tenofovir DF were: Cmax 3190 ng/mL, AUC 34459 ngoh/mL, and Cmin 491 ng/mL. Study was conducted in subjects with HIV-1 infection.NA not available.atenolol50 mg QD, 7-11 (n=19)and 19-23400 mg QD, 1-11(n=19)1.00(0.89, 1.12)0.93(0.85, 1.01)0.74(0.65, 0.86)clarithromycin500 mg BID, 7-10 (n=29)and 18-21400 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)b ddI: 200 mg 1 dose,d4T: 40 mg 1 dose (n=31)400 mg 1 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 1 dose,d4T: 40 mg 1 dose (n=32)400 mg 1 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)efavirenz600 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,2 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,d 1-10 (pm) (n=22),then 400 mg QD with ritonavir 100 mg QD, 11-24 (pm), (simultaneously with efavirenz)(n=14)1.17(1.08, 1.27)1.00(0.91, 1.10)0.58(0.49, 0.69)famotidine40 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),d 7-12 (10 after, h 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,d 1-10 (n=46),d 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,d 1-10 (am) (n=39),d 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,d 1-10 (am)(n=39),d 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),d 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, 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/elbasvirgrazoprevir 200 mg QDd 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 QDd 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)ketoconazole200 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)nevirapinef,g 200 mg BID, 1-23(n=23)300 mg QD with ritonavir 100 mg QD,d 4-13, then400 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)omeprazole40 mg QD, 7-12(n=16)i 400 mg QD,d 1-6 (n=48),d 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)i 300 mg QD with ritonavir 100 mg QD,d 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,d 7-16 (pm) (n=27),d 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,d 7-16 (am) (n=27), then400 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)pitavastatin4 mg QD for days300 mg QD for days1.13(0.96, 1.32)1.06(0.90, 1.26)NArifabutin150 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)rifampin600 mg QD, 17-26(n=16)300 mg QD with ritonavir 100 mg QD,d 7-16 (n=48),d 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)Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZa CoadministeredDrugCoadministered DrugDose/ScheduleREYATAZDose/ScheduleRatio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/withoutREYATAZ;No Effect 1.00Cmax AUCCmin Data provided are under fed conditions unless otherwise noted. 400 mg ddI EC and REYATAZ 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 Cmax, AUC, and Cmin 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 Cmax, AUC, and Cmin 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 in 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 REYATAZ 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 and 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 Cmax 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 REYATAZ was separated by 12 hours. Administration of tenofovir DF and REYATAZ was temporally separated by 12 hours.NA not available.acetaminophen1 BID, 1-20(n=10)300 mg QD with ritonavir 100 mg QD,d 11-20 (n=10)0.87(0.77, 0.99)0.97(0.91, 1.03)1.26(1.08, 1.46)atenolol50 mg QD, 7-11 (n=19)and 19-23400 mg QD, 1-11(n=19)1.34(1.26, 1.42)1.25(1.16, 1.34)1.02(0.88, 1.19)clarithromycin500 mg BID, 7-10 (n=21)and 18-21400 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 (enteric-coated [EC] capsules)b 400 mg 1 (fasted), 8 (fed)(n=34)400 mg QD,d 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)diltiazem180 mg QD, 7-11 (n=28)and 19-23400 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,d 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 norgestimated 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,d 29-42(n=14)ethinyl estradiol:0.84(0.74, 0.95)17-deacetyl norgestimate:f 1.68(1.51, 1.88)ethinyl estradiol:0.81(0.75, 0.87)17-deacetylnorgestimate:f 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/ pibrentasvir300 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)>=14.3g (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)>=2.29g (1.95, 2.68)grazoprevir/elbasvirgrazoprevir 200 mg QD 1-35(n=12)300 mg QD with ritonavir 100 mg QDd 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 QDd 1-35(n=10)300 mg QD with ritonavir 100 mg QDd 1-35(n=10)4.15 (3.46, 4.97)4.76 (4.07, 5.56)6.45(5.51, 7.54)methadoneStable maintenancedose, 1-15(n=16)400 mg QD, 2-15(n=16)(R)-methadoneh 0.91(0.84, 1.0)total: 0.85(0.78, 0.93)(R)-methadoneh 1.03(0.95, 1.10)total: 0.94(0.87, 1.02)(R)-methadoneh 1.11(1.02, 1.20)total: 1.02(0.93, 1.12)nevirapinei,j 200 mg BID, 1-23(n=23)300 mg QD with ritonavir 100 mg QD,d 4-13, then400 mg QD with ritonavir 100 mg QD,d 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)NArifabutin300 mg QD, 1-10then 150 mg QD, 11-20(n=3)600 mg QD,l 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 QD with ritonavir 100 mg QD,d 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)pitavastatin4 mg QDfor days300 mg QDfor days1.60(1.39, 1.85)1.31(1.23, 1.39)NArosiglitazonen mg single dose, 1, 7, 17(n=14)400 mg QD, 2-7, then300 mg QD with ritonavir 100 mg QD,d 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 NArosuvastatin10 mg single dose300 mg QD with ritonavir 100 mg QD for days 7-foldo 3-foldo NAsaquinavirp (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/voxilaprevir400 mg sofosbuvir single dose(n=15)300 mg with 100 mg ritonavir single dose(n=15)1.29(1.09, 1.52)sofosbuvir metaboliteGS-3310071.05(0.99, 1.12)1.40(1.25, 1.57)sofosbuvir metaboliteGS-3310071.25(1.16, 1.36)NA100 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)NA100 mg voxilaprevir single dose(n=15)300 mg with 100 mg ritonavir single dose(n=15)4.42(3.65, 5.35)4.31(3.76, 4.93)NAtenofovir DFq 300 mg QD, 9-16 (n=33)and 24-30(n=33)400 mg QD, 2-16(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)d 25-34 (pm) (n=12)300 mg QD with 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 mg with 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 zidovudine150 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)zidovudineglucuronide: 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). Reyataz Fig 1.

PREGNANCY SECTION.

8.1 Pregnancy . Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk Summary. Atazanavir 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 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 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 PeriodoREYATAZ must be administered with ritonavir in pregnant patients.oFor pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.oNo 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)].. oREYATAZ must be administered with ritonavir in pregnant patients.. oFor pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.. oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.. oNo 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 REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.Hyperbilirubinemia occurs frequently in patients who take REYATAZ [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 REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data].. Data . Human Data In Study AI424-182, REYATAZ 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 REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ 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 2-4%.. 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.

RECENT MAJOR CHANGES SECTION.

Contraindications (4) 9/2020Warnings and Precautions Immune Reconstituted Syndrome (5.10) 9/2020.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONREYATAZ(R) (RAY-ah-taz)(atazanavir)capsulesREYATAZ(R) (RAY-ah-taz)(atazanavir)oral powderImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with REYATAZ. For more information, see Do not take REYATAZ if you and Before taking REYATAZ.What is REYATAZREYATAZ is prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection, in combination with other HIV-1 medicines in adults and children months of age and older and who weigh at least 11 pounds (5 kg). HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).REYATAZ should not be used in children younger than months of age.Do not take REYATAZ if you:oare allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for complete list of ingredients in REYATAZ.oare taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious or life-threatening side effects, or death when used with these medicines:oalfuzosinoamiodarone (when REYATAZ is used with ritonavir)ocisaprideoelbasvir and grazopreviroergot medicines including:dihydroergotamineergonovineergonovine ergotaminemethylergonovine oglecaprevir and pibrentasvir oindinaviroirinotecanolurasidone (when REYATAZ is used with ritonavir)olomitapideolovastatinomidazolam, when taken by mouth for sedationonevirapineopimozideoquinidine (when REYATAZ is used with ritonavir)orifampinosildenafil, when used for the treatment of pulmonary arterial hypertensionosimvastatin oSt. Johns wortotriazolamBefore taking REYATAZ, tell your healthcare provider about all of your medical conditions, including if you:ohave heart problemsohave liver problems, including hepatitis or virus infectionohave phenylketonuria (PKU). The artificial sweetener aspartame in REYATAZ oral powder contains phenylalanine, which can be harmful to people with PKU.ohave kidney problemsoare receiving dialysis treatmentohave diabetesohave hemophiliaoare pregnant or plan to become pregnant.oREYATAZ must be taken with ritonavir during pregnancy.oHormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ.oPregnancy Exposure Registry. There is pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby.oTalk to your healthcare provider about how you can take part in this registry.oAfter your baby is born, tell your healthcare provider if your babys skin or the white part of their eyes turns yellow.oare breastfeeding or plan to breastfeed. Do not breastfeed if you are taking REYATAZ.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. REYATAZ can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with REYATAZ. Keep list of your medicines to show your healthcare provider and pharmacist. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with REYATAZ.oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take REYATAZ with other medicines.How should take REYATAZoTake REYATAZ exactly as your healthcare provider tells you to.oDo not change your dose or stop taking REYATAZ unless your healthcare provider tells you to.oStay under the care of your healthcare provider during treatment with REYATAZ.oREYATAZ must be used with other HIV-1 medicines.oTake REYATAZ time each day.oREYATAZ comes as capsules and oral powder.oTake REYATAZ capsules and oral powder with food.oSwallow the capsules whole. Do not open the capsules.oREYATAZ oral powder must be mixed with food or liquid. Your childs healthcare provider will prescribe the right dose of REYATAZ based on your childs weight. See the detailed Instructions for Use that comes with REYATAZ oral powder for information about the correct way to mix and give dose of REYATAZ oral powder to your child. oREYATAZ oral powder must be taken with ritonavir.oIf you miss dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take doses at the same time.oIf you take too much REYATAZ, call your healthcare provider or go to the nearest hospital emergency room right away.When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV-1 in your blood may increase if the medicine is stopped for even short time. The virus may become resistant to REYATAZ and harder to treat.What are the possible side effects of REYATAZREYATAZ can cause serious side effects, including:oA change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of heart problem.oSkin rash. Skin rash is common with REYATAZ but can sometimes be severe. Severe rash may develop with other symptoms which could be serious. If you develop severe rash or rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider or go to the nearest hospital emergency room right away:ogeneral feeling of discomfort or flu-like symptomsofeveromuscle or joint achesored or inflamed eyes, like pink eye (conjunctivitis)oblistersomouth soresoswelling of your faceopainful, warm, or red lump under your skinoLiver problems. If you have liver problems, including hepatitis or infection, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:odark tea-colored urineoyour skin or the white part of your eyes turns yellowolight colored stoolsonauseaoitchingostomach-area painoChronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment. Drink plenty of fluids during treatment with REYATAZ.oKidney stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate.oGallbladder stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of gallbladder problem which may include:opain in the right or middle upper stomach areaofeveronausea and vomitingoyour skin or the white part of your eyes turns yellowoYellowing of your skin or the white part of your eyes is common with REYATAZ but may be symptom of serious problem. These symptoms may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.oNew or worsening diabetes and high blood sugar (hyperglycemia) have happened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have changes to their dose of their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking REYATAZ.oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ. oChanges in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.oIncreased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ.The most common side effects of REYATAZ include:onauseaoheadacheostomach-area painovomitingotrouble sleepingonumbness, tingling, or burning of hands or feetodizzinessomuscle painodiarrheaodepressionofeverTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of REYATAZ. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store REYATAZREYATAZ capsules:oStore REYATAZ capsules at room temperature, between 68F to 77F (20C to 25C).oKeep capsules in tightly closed container.oThe REYATAZ bottle comes with child-resistant closure.REYATAZ oral powder:oStore REYATAZ oral powder at temperature of 68F to 86F (20C to 30C).oStore REYATAZ oral powder in the original packet. Do not open until ready to use.oAfter REYATAZ oral powder is mixed with food or liquid it may be kept at temperature of 68F to 86F (20C to 30C) for up to hour. Take REYATAZ oral powder within hour after mixing with food or liquid.Keep REYATAZ and all medicines out of the reach of children.General information about the safe and effective use of REYATAZMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use REYATAZ for condition for which it was not prescribed. Do not give REYATAZ to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about REYATAZ that is written for health professionals.For more information, go to www.reyataz.com or call 1-800-321-1335.What are the ingredients in REYATAZActive ingredient: atazanavir sulfateInactive ingredients:REYATAZ capsules: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.REYATAZ oral powder: aspartame, sucrose, and orange-vanilla flavor.Distributed by:Bristol-Myers Squibb Company, Princeton, NJ 08543 USA.REYATAZ(R) is registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: September 2020[print code]. oare allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for complete list of ingredients in REYATAZ.. oare taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious or life-threatening side effects, or death when used with these medicines:. oalfuzosin. oamiodarone (when REYATAZ is used with ritonavir). ocisapride. oelbasvir and grazoprevir. oergot medicines including:dihydroergotamineergonovineergonovine ergotaminemethylergonovine dihydroergotamine. ergonovine. ergonovine ergotamine. methylergonovine oglecaprevir and pibrentasvir oindinavir. oirinotecan. olurasidone (when REYATAZ is used with ritonavir). olomitapide. olovastatin. omidazolam, when taken by mouth for sedation. onevirapine. opimozide. oquinidine (when REYATAZ is used with ritonavir). orifampin. osildenafil, when used for the treatment of pulmonary arterial hypertension. osimvastatin oSt. Johns wort. otriazolam. ohave heart problems. ohave liver problems, including hepatitis or virus infection. ohave phenylketonuria (PKU). The artificial sweetener aspartame in REYATAZ oral powder contains phenylalanine, which can be harmful to people with PKU.. ohave kidney problems. oare receiving dialysis treatment. ohave diabetes. ohave hemophilia. oare pregnant or plan to become pregnant.oREYATAZ must be taken with ritonavir during pregnancy.oHormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ.oPregnancy Exposure Registry. There is pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby.oTalk to your healthcare provider about how you can take part in this registry.oAfter your baby is born, tell your healthcare provider if your babys skin or the white part of their eyes turns yellow.. oREYATAZ must be taken with ritonavir during pregnancy.. oHormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ.. oPregnancy Exposure Registry. There is pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby.. oTalk to your healthcare provider about how you can take part in this registry.. oAfter your baby is born, tell your healthcare provider if your babys skin or the white part of their eyes turns yellow.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you are taking REYATAZ.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. REYATAZ can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby.. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. REYATAZ can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with REYATAZ.. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take REYATAZ with other medicines.. oTake REYATAZ exactly as your healthcare provider tells you to.. oDo not change your dose or stop taking REYATAZ unless your healthcare provider tells you to.. oStay under the care of your healthcare provider during treatment with REYATAZ.. oREYATAZ must be used with other HIV-1 medicines.. oTake REYATAZ time each day.. oREYATAZ comes as capsules and oral powder.. oTake REYATAZ capsules and oral powder with food.. oSwallow the capsules whole. Do not open the capsules.. oREYATAZ oral powder must be mixed with food or liquid. Your childs healthcare provider will prescribe the right dose of REYATAZ based on your childs weight. See the detailed Instructions for Use that comes with REYATAZ oral powder for information about the correct way to mix and give dose of REYATAZ oral powder to your child. oREYATAZ oral powder must be taken with ritonavir.. oIf you miss dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take doses at the same time.. oIf you take too much REYATAZ, call your healthcare provider or go to the nearest hospital emergency room right away.. oA change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of heart problem.. oSkin rash. Skin rash is common with REYATAZ but can sometimes be severe. Severe rash may develop with other symptoms which could be serious. If you develop severe rash or rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider or go to the nearest hospital emergency room right away:. ogeneral feeling of discomfort or flu-like symptoms. ofever. omuscle or joint aches. ored or inflamed eyes, like pink eye (conjunctivitis). oblisters. omouth sores. oswelling of your face. opainful, warm, or red lump under your skin. oLiver problems. If you have liver problems, including hepatitis or infection, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:. odark tea-colored urine. oyour skin or the white part of your eyes turns yellow. olight colored stools. onausea. oitching. ostomach-area pain. oChronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment. Drink plenty of fluids during treatment with REYATAZ.. oKidney stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate.. oGallbladder stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of gallbladder problem which may include:. opain in the right or middle upper stomach area. ofever. onausea and vomiting. oyour skin or the white part of your eyes turns yellow. oYellowing of your skin or the white part of your eyes is common with REYATAZ but may be symptom of serious problem. These symptoms may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.. oNew or worsening diabetes and high blood sugar (hyperglycemia) have happened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have changes to their dose of their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking REYATAZ.. oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ. oChanges in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.. oIncreased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ.. onausea. oheadache. ostomach-area pain. ovomiting. otrouble sleeping. onumbness, tingling, or burning of hands or feet. odizziness. omuscle pain. odiarrhea. odepression. ofever. oStore REYATAZ capsules at room temperature, between 68F to 77F (20C to 25C).. oKeep capsules in tightly closed container.. oThe REYATAZ bottle comes with child-resistant closure.. oStore REYATAZ oral powder at temperature of 68F to 86F (20C to 30C).. oStore REYATAZ oral powder in the original packet. Do not open until ready to use.. oAfter REYATAZ oral powder is mixed with food or liquid it may be kept at temperature of 68F to 86F (20C to 30C) for up to hour. Take REYATAZ oral powder within hour after mixing with food or liquid.

SPL UNCLASSIFIED SECTION.

2.1 Overview oREYATAZ capsules and oral powder must be taken with food.oDo not open the capsules.oThe recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)].oREYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)].oREYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than kg [see Dosage and Administration (2.5)].oEfficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.. oREYATAZ capsules and oral powder must be taken with food.. oDo not open the capsules.. oThe recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)].. oREYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)].. oREYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than kg [see Dosage and Administration (2.5)].. oEfficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . oPregnancy: 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) oLactation: Breastfeeding is not recommended. (8.2) oHepatitis or co-infection: Monitor liver enzymes. (5.4, 6.1) oRenal impairment: REYATAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis. (2.7, 8.7) oHepatic impairment: REYATAZ is not recommended in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment. (2.8, 8.8) oPregnancy: 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) oLactation: Breastfeeding is not recommended. (8.2) oHepatitis or co-infection: Monitor liver enzymes. (5.4, 6.1) oRenal impairment: REYATAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis. (2.7, 8.7) oHepatic impairment: REYATAZ is not recommended in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment. (2.8, 8.8) 8.1 Pregnancy . Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk Summary. Atazanavir 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 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 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 PeriodoREYATAZ must be administered with ritonavir in pregnant patients.oFor pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.oNo 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)].. oREYATAZ must be administered with ritonavir in pregnant patients.. oFor pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.. oFor treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend REYATAZ dose for use with both an H2-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.. oNo 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 REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.Hyperbilirubinemia occurs frequently in patients who take REYATAZ [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 REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data].. Data . Human Data In Study AI424-182, REYATAZ 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 REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ 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 2-4%.. 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.. 8.4 Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, months of age and older weighing at least kg. REYATAZ 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 REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)].The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least months of age and older weighing at least kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [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 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.. 8.5 Geriatric Use Clinical studies of REYATAZ 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 Cmax and AUC, dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ 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 A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 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 REYATAZ 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 REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ 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 . oCardiac 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) oSevere Skin Reactions: Discontinue if severe rash develops. (5.2, 17) oHyperbilirubinemia: 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) oPhenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3) oHepatotoxicity: 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) oChronic kidney disease has been reported during postmarketing surveillance in patients with 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 REYATAZ in patients with progressive renal disease. (5.5) oNephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6) oThe concomitant use of REYATAZ 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)oPatients receiving REYATAZ 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).oHemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.12) oCardiac 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) oSevere Skin Reactions: Discontinue if severe rash develops. (5.2, 17) oHyperbilirubinemia: 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) oPhenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3) oHepatotoxicity: 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) oChronic kidney disease has been reported during postmarketing surveillance in patients with 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 REYATAZ in patients with progressive renal disease. (5.5) oNephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6) oThe concomitant use of REYATAZ 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). oPatients receiving REYATAZ 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).. oHemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.12) 5.1 Cardiac Conduction Abnormalities REYATAZ 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)].. 5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection treated with REYATAZ. 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 REYATAZ 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 REYATAZ [see Contraindications (4) and Adverse Reactions (6.1)]. REYATAZ should be discontinued if severe rash develops.. 5.3 Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.. 5.4 Hepatotoxicity 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 REYATAZ 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 REYATAZ 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 REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ 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 REYATAZ with ritonavir, respectively. These interactions may lead to:oclinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.oclinically significant adverse reactions from greater exposures of REYATAZ with ritonavir.oloss of therapeutic effect of REYATAZ 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 REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].. oclinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.. oclinically significant adverse reactions from greater exposures of REYATAZ with ritonavir.. oloss of therapeutic effect of REYATAZ with ritonavir and possible development of resistance.. 5.8 Hyperbilirubinemia Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. 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 REYATAZ 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 patients with 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 REYATAZ. 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, 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.. 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)].