REYATAZ

Absorption

Atazanavir is rapidly absorbed with a T_max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C_max values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 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 a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C_max relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C_max relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and C_max by approximately one-half compared to the fasting state.

Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C_max and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C_max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T_max increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state.

Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with REYATAZ 400 mg once daily with a 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 a 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 volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a 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 C_max 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 a 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 C_max, AUC, and C_min 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 HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Dosage and Administration (2.6).]

Hepatic Impairment

REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A 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 (2.7).]

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses. [See Dosage and Administration (2.4) .]

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses. [See Dosage and Administration (2.4) .]

Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 20.

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K_inact value of 0.05 to 0.06 min^-1 and K_i value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (K_i=1.9 µM) and CYP2C8 (K_i=2.1 µM).

Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

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, C_max, and C_min are summarized in Tables 21 and 22. For information regarding clinical recommendations, see Drug Interactions (7) .

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 a mean 50% effective concentration (EC₅₀) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV 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 ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, 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 a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV 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 ATV and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Patients: 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 HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.

Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV 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 ATV/RTV-virologic failure isolates had baseline phenotypic ATV 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 a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV 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 LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV 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 LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV 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 patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV 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 Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients 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 patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir 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 ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV 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 patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451(PRINCE II): No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV 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 patients, 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 ATV susceptibility before initiation of ATV/RTV 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 patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV 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 patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1–2 PI substitutions, including one of these substitutions.

The response rates of antiretroviral-experienced patients 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 a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

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.

14 CLINICAL STUDIES

14.1 Adult Patients without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was a 96-week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a 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: 2 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.

Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm³ for the REYATAZ/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 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a 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.

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV 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 was a 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 patients. Patients had a 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: 4 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.

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 Patients with Prior Antiretroviral Therapy

Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 was a 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), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART 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/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of quantification. [See Microbiology, Tables 24 and 25 (12.4) .]

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

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for 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 patients 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: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients 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 patients with prior virologic failure and is not recommended for such patients.

14.3 Pediatric Patients

Pediatric Trials with REYATAZ Capsules

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (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) patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV 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 patients and 220 cells/mm³ in antiretroviral-experienced patients.

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.

• •AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
• •AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age

In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.

Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm³ (10.5%) in antiretroviral-naive patients and 228 cells/mm³ (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.

16 HOW SUPPLIED/STORAGE AND HANDLING

REYATAZ Capsules

REYATAZ^® (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.

Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [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 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See Dosage and Administration (2.4).]

Store REYATAZ oral powder below 30°C (86°F). Once the REYATAZ oral powder is mixed with food or beverage, it may be kept at room temperature 20°C to 30°C (68°F-86°F) for up to 1 hour prior to administration. Store REYATAZ oral powder in the original packet and do not open until ready to use.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use).

A statement to patients and healthcare providers is included on the product’s label: ALERT: Find out about medicines that should NOT be taken with REYATAZ^® .

REYATAZ is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a healthcare provider when using REYATAZ.

Patients should be advised to avoid doing things that can spread HIV infection to others.

• • Do not share or re-use needles or other injection equipment.
• • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• • Do not breastfeed. It is not known if REYATAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk.

Dosing Instructions

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a healthcare provider while using REYATAZ. Patients should be advised 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. Patients should not alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

REYATAZ oral powder is available for pediatric patients who are 3 months and older weighing 10 kg to less than 25 kg. Caregivers should be advised on how to mix the REYATAZ oral powder with a food or beverage such as milk or water for infants and young children who can take solid foods or drink liquids from a cup. For infants who cannot take solid food or drink from a cup, the powder formulation mixed in liquid infant formula should be given with an oral dosing syringe. Caregivers should carefully follow the Instructions for Use and storage of the powder [see Dosage and Administration (2.4) and FDA-approved patient labeling (Patient Information and Instructions for Use)].

Caregivers of patients with phenylketonuria should be advised that REYATAZ oral powder contains phenylalanine.

Patients or caregivers should call their healthcare provider or pharmacist if they have any questions.

Drug Interactions

REYATAZ may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.

Patients should be informed that REVATIO^® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS^®, LEVITRA^®, or VIAGRA^® (used to treat erectile dysfunction), or ADCIRCA^® (used to treat pulmonary arterial hypertension).

Cardiac Conduction Abnormalities

Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.

Rash

Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.

Hyperbilirubinemia

Patients should be informed 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.

Nephrolithiasis and Cholelithiasis

Patients should be informed 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.

Fat Redistribution

Patients should be informed 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.

PATIENT INFORMATION

REYATAZ^® (RAY-ah-taz)
(atazanavir)
capsules

REYATAZ^® (RAY-ah-taz)
(atazanavir)
oral powder

Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with REYATAZ. For more information, see “Who should not take REYATAZ?” and “What should I tell my healthcare provider before taking REYATAZ?”

Read this Patient Information before you start taking REYATAZ and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is REYATAZ?

REYATAZ is a prescription HIV-1 (Human Immunodeficiency Virus) medicine that is used with other antiretroviral medicines to treat HIV-1 infection in adults and children 3 months of age and older and who weigh at least 22 pounds (10 kg).

HIV is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

REYATAZ should not be used in children younger than 3 months of age.

When used with other antiretroviral medicines to treat HIV infection, REYATAZ may help:

• •reduce the amount of HIV in your blood. This is called viral load.
• •increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

REYATAZ does not cure HIV infection or AIDS. You must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV infection to others:

• •Do not share or re-use needles or other injection equipment.
• •Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• •Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

Who should not take REYATAZ?

Do not take REYATAZ if you:

• •are allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for a complete list of ingredients in REYATAZ.
• •are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious life-threatening side effects or death when used with these medicines:
  • •alfuzosin (UROXATRAL^®)
  • •cisapride (PROPULSID^®)
  • •ergot medicines including:
    • •ergotamine tartrate (CAFERGOT^®, MIGERGOT^®, ERGOMAR^®, ERGOSTAT^®, MEDIHALER^®, Ergotamine, WIGRAINE^®, WIGRETTES^®)
    • •dihydroergotamine mesylate (D.H.E. 45^®, MIGRANAL^®)
    • •methylergonovine (METHERGINE^®)
  • •indinavir (CRIXIVAN^®)
  • •irinotecan (CAMPTOSAR^®)
  • •lovastatin (ADVICOR^®, ALTOPREV^®, MEVACOR^®)
  • •midazolam (VERSED^®), when taken by mouth for sedation
  • •nevirapine (VIRAMUNE^®, VIRAMUNE XR^®)
  • •pimozide (ORAP^®)
  • •rifampin (RIMACTANE^®, RIFADIN^®, RIFATER^®, RIFAMATE^®)
  • •sildenafil (REVATIO^®), when used for the treatment of pulmonary arterial hypertension
  • •simvastatin (ZOCOR^®, VYTORIN, SIMCOR)
  • •St. John’s wort (Hypericum perforatum)
  • •triazolam (HALCION^®)

Serious problems can happen if you or your child take any of the medicines listed above with REYATAZ.

What should I tell my healthcare provider before taking REYATAZ?

Before taking REYATAZ, tell your healthcare provider if you:

• •have heart problems
• •have liver problems, including hepatitis B or C virus infection
• •have phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine as part of the artificial sweetener aspartame. The artificial sweetener can be harmful to people with PKU.
• •are receiving dialysis treatment
• •have diabetes
• •have hemophilia
• •have any other medical conditions
• •are pregnant or plan to become pregnant. It is not known if REYATAZ will harm your unborn baby. Pregnant women have developed a serious condition called lactic acidosis (a build-up of lactic acid in the blood) when taking REYATAZ with other HIV medicines called nucleoside analogues.
  • • Hormonal 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.
  • • Pregnancy Registry. There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
  • • After your baby is born, tell your healthcare provider if your baby’s skin or the white part of his/her eyes turns yellow.
• •are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking REYATAZ. You should not breastfeed if you have HIV because of the risk of passing HIV to your baby. It is not known if REYATAZ passes 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.

REYATAZ may affect the way other medicines work, and other medicines may affect how REYATAZ works and may cause serious side effects. If you take certain medicines with REYATAZ, the amount of REYATAZ in your body may be too low and it may not work to help control your HIV infection. The HIV virus in your body may become resistant to REYATAZ or other HIV medicines that are like it. Especially tell your healthcare provider if you take any of the medicines below:

The following medicines should not be taken during your treatment with REYATAZ:

• •boceprevir (VICTRELIS^®)
• •salmeterol (SEREVENT DISKUS^®) and salmeterol with fluticasone (ADVAIR DISKUS^®, ADVAIR HFA^®)
• •voriconazole (VFEND^®)

If you take any of the following medicines during treatment with REYATAZ, your healthcare provider may need to change the dose of the medicine or change the dose of REYATAZ, or your healthcare provider may need to monitor you more closely:

• •medicines used to treat abnormal heart rhythm:
  • •amiodarone (CORDARONE^®, NEXTERONE^®, PACERONE^®)
  • •lidocaine
  • •quinidine
• •allergy or asthma medicines (nasal spray or inhaled treatment):
  • •fluticasone propionate (FLONASE^®, FLOVENT DISKUS^®, FLOVENT HFA^®)
• •an antibiotic used to treat tuberculosis (TB):
  • •rifabutin (MYCOBUTIN^®)
• •the anticoagulant (blood thinner) medicine:
  • •warfarin (COUMADIN^®, JANTOVEN^®)
• •antidepressant medicines:
  • •amitriptyline
  • •desipramine (NORPRAMIN^®)
  • •doxepin (SILENOR^®)
  • •trazodone (OLEPTRO^®)
  • •trimipramine (SURMONTIL^®)
  • •imipramine (TOFRANIL^®, TOFRANIL-PM^®)
  • •protriptyline (VIVACTIL^®)
• •the chest pain medicine:
  • •bepridil (VASCOR^®)
• •cholesterol-lowering medicines:
  • •atorvastatin (LIPITOR^®)
  • •rosuvastatin (CRESTOR^®)
• •erectile dysfunction medicines:
  • •sildenafil (VIAGRA^®)
  • •tadalafil (CIALIS^®)
  • •vardenafil (LEVITRA^®, STAXYN^®)
• •a medicine for gout or treatment of familial Mediterranean fever:
  • •colchicine (COLCRYS^®)
• •organ transplant rejection medicines:
  • •cyclosporine (SANDIMMUNE^®, NEORAL^®, GENGRAF^®)
  • •sirolimus (RAPAMUNE^®)
  • •tacrolimus (PROGRAF^®, ASTAGRAF XL^®)
• •pain and addiction medicines:
  • •buprenorphine or buprenorphine/naloxone (BUPRENEX^®, BUTRANS^®, ZUBSOLV^®, SUBOXONE^®)
• •pulmonary arterial hypertension medicines:
  • •bosentan (TRACLEER^®)
  • •tadalafil (ADCIRCA^®)
• •medicine to treat fungal infections
  • •ketoconazole (NIZORAL^®)
  • •itraconazole (SPORANOX^®, ONMEL^®)

People who take sildenafil (VIAGRA^®), tadalafil (CIALIS^®, ADCIRCA^®) or vardenafil (LEVITRA^®, STAXYN^®) with REYATAZ may have a higher risk of certain side effects. Tell your healthcare provider right away if you take any of these medicines and have any of the following side effects:

• • •lightheadedness, especially when standing
  • •fainting
  • •changes in your vision
  • •an erection that lasts more than 4 hours

If you take any of the following medicines, your healthcare provider may change the dose or the time you take REYATAZ or the other medicine:

• •antiepileptic medicines:
  • •carbamazepine (CARBATROL^®, EPITOL^®, TEGRETOL^®, TEGRETOL-XR^®, EQUETRO^®, TERIL^®)
  • •phenytoin (DILANTIN^®)
  • •lamotrigine (LAMICTAL^®, LAMICTAL CD^®, LAMICTAL XR^®, LAMICTAL ODT^®)
• •calcium channel blockers such as:
  • •diltiazem (CARDIZEM^®, CARDIZEM CD^®, CARDIZEM LA^®, TIAZAC^®, CARTIA XT^®, DILACOR XR^®, DILT-CD^®, DILTZAC^®, TAZTIA XT^®)
  • •verapamil (COVERA-HS^®, CALAN^®, CALAN SR^®, VERALAN^®, VERELAN PM^®)
  • •felodipine (PLENDIL^®)
  • •nifedipine (ADALAT CC^®, AFEDITAB CR^®, PROCARDIA^®, PROCARDIA XL^®)
  • •nicardipine (CARDENE^®, CARDENE SR^®)
• •indigestion, heartburn, or ulcer medicines:
  • •cimetidine (TAGAMET^®)
  • •esomeprazole (NEXIUM^®)
  • •famotidine (PEPCID^®, PEPCID AC^®)
  • •rabeprazole (ACIPHEX^®, ACIPHEX SPRINKLE™)
  • •nizatidine (AXID^®)
  • •lansoprazole (PREVACID^®)
  • •omeprazole (PRILOSEC^®)
  • •pantoprazole (PROTONIX^®)
  • •ranitidine (ZANTAC^® )
• •antacids or buffered medicines
• •antibiotics or antiviral medicines
  • •clarithromycin (BIAXIN^®, BIAXIN XL^®)
  • •didanosine (VIDEX^®, VIDEX EC^®)
  • •efavirenz (SUSTIVA^®)
  • •rifabutin (MYCOBUTIN^®)
  • •ritonavir (NORVIR^®)
  • •saquinavir (INVIRASE^®)
  • •tenofovir disoproxil fumarate (VIREAD^®)

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

Your healthcare provider and your pharmacist can tell you if you can take these medicines with REYATAZ. Do not start any new medicines while you are taking REYATAZ without first talking with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that can interact with REYATAZ.

How should I take REYATAZ?

• • Take REYATAZ exactly as your healthcare provider tells you to.
• • Do not change your dose or stop taking REYATAZ unless your healthcare provider tells you to.
• •Stay under the care of your healthcare provider during treatment with REYATAZ.
• •REYATAZ must be used with other antiretroviral medicines.
• •Take REYATAZ 1 time each day.
• •REYATAZ comes as capsules and oral powder.
• • Take REYATAZ capsules and oral powder with food.
• •Swallow the capsules whole. Do not open the capsules.
• •REYATAZ oral powder must be mixed with food or liquid. Your child’s healthcare provider will prescribe the right dose of REYATAZ based on your child’s weight.
• •REYATAZ oral powder must be taken with ritonavir.
• •If you miss a dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take 2 doses at the same time.
• • If 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 a short time. The virus may become resistant to REYATAZ and harder to treat.

What are the possible side effects of REYATAZ?

REYATAZ can cause serious side effects, including:

• • A 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 a heart problem.
• • Skin rash. Skin rash is common with REYATAZ but can sometimes be severe. Skin rash usually goes away within 2 weeks without any change in treatment. Severe rash may develop in association with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider right away:
  • •general feeling of discomfort or “flu-like” symptoms
  • •fever
  • •muscle or joint aches
  • •red or inflamed eyes, like “pink eye” (conjunctivitis)
  • •blisters
  • •mouth sores
  • •swelling of your face
  • •painful, warm, or red lump under your skin
• • Yellowing of your skin or the white part of your eyes is common with REYATAZ but may be a symptom of a serious problem. These effects may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Although these effects may not be damaging to your liver, skin, or eyes, tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.
• • Liver problems. If you have liver problems, including hepatitis B or C 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:
  • •your skin or the white part of your eyes turn yellow
  • •dark “tea-colored” urine
  • •light colored stools
  • •nausea
  • •itching
  • •stomach-area pain
• • Kidney stones have happened in some people who take REYATAZ. 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.
• • Gallbladder problems have happened in some people who take REYATAZ. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include:
  • •pain in the right or middle upper stomach-area
  • •fever
  • •nausea and vomiting
  • •your skin or the white part of your eyes turns yellow
• • Diabetes and high blood sugar (hyperglycemia) have happened or have worsened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have had to change their diabetes medicine.
• • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting your HIV medicine.
• • Changes in body fat can happen in people taking HIV medicine. 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 cause and long-term health effects of these conditions are not known.
• • Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ.

The most common side effects of REYATAZ include:

Tell 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 I store REYATAZ?

REYATAZ capsules:

• •Store REYATAZ capsules at room temperature, between 68°F to 77°F (20°C to 25°C).
• •Keep capsules in a tightly closed container.

REYATAZ oral powder:

• •Store REYATAZ oral powder below 86°F (30°C).
• •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 room temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid.

Keep REYATAZ and all medicines out of the reach of children.

General information about REYATAZ

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REYATAZ for a 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 REYATAZ?

Active ingredient: atazanavir sulfate

Inactive 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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Distributed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543  USA

1341313

Revised: June 2014

VIDEX^® and REYATAZ^® are registered trademarks of Bristol-Myers Squibb Company. COUMADIN^® and SUSTIVA^® are registered trademarks of Bristol-Myers Squibb Pharma Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

Instructions for Use

REYATAZ ^® (RAY-ah-taz)
(atazanavir)
oral powder

Read this Instructions for Use before you prepare your child’s first dose of REYATAZ oral powder, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask your child’s healthcare provider or pharmacist if you have questions about how to mix or give a dose of REYATAZ oral powder.

Important information:

• •For more information about REYATAZ oral powder, see the Patient Information leaflet.
• •REYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, the child must eat food right after taking REYATAZ oral powder.
• •REYATAZ oral powder must be taken with ritonavir.
• •Talk with your child’s 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 a liquid (milk, infant formula, or water) in young children and infants who can take food.

• •Infants less than 6 months old and who cannot eat solid food or drink from a cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe.
• •REYATAZ oral powder that is mixed in infant formula or liquid should not be given using a baby bottle.

When preparing REYATAZ oral powder with either food or liquid, choose a clean, flat work surface. Place a 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 a dose of REYATAZ oral powder mixed with food:

Before you prepare a dose of REYATAZ oral powder mixed with food, gather the following supplies:

Preparing a dose of REYATAZ oral powder mixed with liquid in a small drinking cup:

Before you prepare a dose of REYATAZ oral powder mixed with liquid in a small drinking cup, gather the following supplies:

If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.

Preparing a dose of REYATAZ oral powder mixed with liquid infant formula using an oral dosing syringe and a small medicine cup:

Before you prepare a dose of REYATAZ oral powder mixed with infant formula using an oral dosing syringe, gather the following supplies:

How should I store REYATAZ oral powder?

• •Store REYATAZ oral powder below 86°F (30°C).
• •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 room temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 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 Company
Princeton, NJ 08543  USA

Product of Ireland

1341313

Issued: June 2014

REYATAZ 100 mg Capsules Representative Packaging

See HOW SUPPLIED section for a complete list of available packages of REYATAZ.

NDC 0003-3623-12
Bristol-Myers Squibb
60 Capsules
REYATAZ^®
(atazanavir sulfate)
100 mg
Rx only
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that should NOT be taken with REYATAZ^®

REYATAZ 150 mg Capsules Representative Packaging

NDC 0003-3624-12
Bristol-Myers Squibb
60 Capsules
REYATAZ^®
(atazanavir sulfate)
150 mg
Rx only
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that should NOT be taken with REYATAZ^®

REYATAZ 200 mg Capsules Representative Packaging

NDC 0003-3631-12
Bristol-Myers Squibb
60 Capsules
REYATAZ^®
(atazanavir sulfate)
200 mg
Rx only
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that should NOT be taken with REYATAZ^®

REYATAZ 300 mg Capsules Representative Packaging

NDC 0003-3622-12
Bristol-Myers Squibb
30 Capsules
REYATAZ^®
(atazanavir sulfate)
300 mg
Rx only
Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that should NOT be taken with REYATAZ^®