FDA label 86549ef5-0809-3c5a-e053-2991aa0a16d3

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

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: cardiac conduction abnormalities [see Warnings and Precautions (5.1)] rash [see Warnings and Precautions (5.2)] chronic kidney disease [see Warnings and Precautions (5.5)] hyperbilirubinemia [see Warnings and Precautions (5.8)] nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 a 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 Patients The safety profile of atazanavir in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received atazanavir 300 mg with ritonavir 100 mg and 1089 patients received atazanavir 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-naive patients receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactions Includes events of possible, probable, certain, or unknown relationship to treatment regimen. of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients, Based on the regimen containing atazanavir. Study AI424-138 96 weeks Median time on therapy. atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF with emtricitabine As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily. (n=441) 96 weeks lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir DF with emtricitabine (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% * None reported in this treatment arm. Table 8: Selected Adverse Reactions Includes events of possible, probable, certain, or unknown relationship to treatment regimen. of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients, Based on regimens containing atazanavir. Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeks Median time on therapy. atazanavir 400 mg once daily + lamivudine + zidovudine As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily. (n=404) 64 weeks efavirenz 600 mg once daily + lamivudine + zidovudine (n=401) 120 weeks , Includes long-term follow-up. atazanavir 400 mg once daily + stavudine + lamivudine or didanosine (n=279) 73 weeks , nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% * None reported in this treatment arm. Adverse Reactions in Treatment-Experienced Adult Patients The safety profile of atazanavir in treatment-experienced adults is based on 119 HIV-1 infected patients in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced patients receiving atazanavir/ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions Includes events of possible, probable, certain, or unknown relationship to treatment regimen. of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Patients, Based on the regimen containing atazanavir. Study AI424-045 48 weeks Median time on therapy. atazanavir/ritonavir 300/100 mg once daily + tenofovir DF + NRTI (n=119) 48 weeks lopinavir/ritonavir 400/100 mg twice daily As a fixed-dose combination. + tenofovir DF + NRTI (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * * None reported in this treatment arm. Laboratory Abnormalities in Treatment-Naive Patients The percentages of adult treatment-naive patients treated with combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) with Grade 3 to 4 laboratory abnormalities are presented in Tables 10 and 11, respectively. Table 10: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients, Based on the regimen containing atazanavir. Study AI424-138 Variable Limit ULN = upper limit of normal. 96 weeks Median time on therapy. atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF with emtricitabine As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily. (n=441) 96 weeks lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir DF with emtricitabine (n=437) Chemistry High SGOT/AST ≥5.1 x ULN 3% 1% SGPT/ALT ≥5.1 x ULN 3% 2% Total Bilirubin ≥2.6 x ULN 44% <1% Lipase ≥2.1 x ULN 2% 2% Creatine Kinase ≥5.1 x ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients, Based on regimen(s) containing atazanavir. Studies AI424-034, AI424-007, and AI424-008 Variable Limit ULN = upper limit of normal. Study AI424-034 Studies AI424-007, -008 64 weeks Median time on therapy. atazanavir 400 mg once daily + lamivudine + zidovudine As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily. (n=404) 64 weeks efavirenz 600 mg once daily + lamivudine + zidovudine (n=401) 120 weeks , Includes long-term follow-up. atazanavir 400 mg once daily + stavudine + lamivudine or + stavudine + didanosine (n=279) 73 weeks , nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or + stavudine + didanosine (n=191) Chemistry High SGOT/AST ≥5.1 x ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 x ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 x ULN 35% <1% 47% 3% Amylase ≥2.1 x ULN * * 14% 10% Lipase ≥2.1 x ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 x ULN 6% 6% 11% 9% Total Cholesterol ≥240 mg/dL 6% 24% 19% 48% Triglycerides ≥751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8.0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% * None reported in this treatment arm. Change in Lipids from Baseline in Treatment-Naive Patients For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 atazanavir/ritonavir Atazanavir 300 mg with ritonavir 100 mg once daily with the fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily. , Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the atazanavir/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir/ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir/ritonavir arm. lopinavir/ritonavir , Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir DF, 200 mg emtricitabine once daily. Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL (n=428 Number of patients with LDL-cholesterol measured. ) mg/dL (n=372 ) Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. (n=372 ) mg/dL (n=342 ) Change (n=342 ) mg/dL (n=424 ) mg/dL (n=335 ) Change (n=335 ) mg/dL (n=291 ) Change (n=291 ) LDL-Cholesterol Fasting. 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides 126 145 +15% 140 +13% 129 194 +52% 184 +50% Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 atazanavir Atazanavir 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily. , Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the atazanavir arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the atazanavir arm. efavirenz , Efavirenz 600 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily. Baseline Week 48 Week 48 Baseline Week 48 Week 48 mg/dL (n=383 Number of patients with LDL-cholesterol measured. ) mg/dL (n=283 ) Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. (n=272 ) mg/dL ( n=378 ) mg/dL (n=264 ) Change (n=253 ) LDL-Cholesterol Fasting. 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides 138 124 -9% 129 168 +23% Laboratory Abnormalities in Treatment-Experienced Patients The percentages of adult treatment-experienced patients treated with combination therapy including atazanavir/ritonavir with Grade 3 to 4 laboratory abnormalities are presented in Table 14. Table 14: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Patients, Study AI424-045 Based on regimen(s) containing atazanavir. Variable Limit ULN = upper limit of normal. 48 weeks Median time on therapy. atazanavir /ritonavir 300/100 mg once daily + tenofovir DF + NRTI (n=119) 48 weeks lopinavir/ritonavir 400/100 mg twice daily As a fixed-dose combination. + tenofovir DF + NRTI (n=118) Chemistry High SGOT/AST ≥5.1 x ULN 3% 3% SGPT/ALT ≥5.1 x ULN 4% 3% Total Bilirubin ≥2.6 x ULN 49% <1% Lipase ≥2.1 x ULN 5% 6% Creatine Kinase ≥5.1 x ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% Change in Lipids from Baseline in Treatment-Experienced Patients For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with atazanavir/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 atazanavir/ritonavir Atazanavir 300 mg once daily + ritonavir + tenofovir DF + 1 NRTI. , Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the atazanavir/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir/ritonavir arm. lopinavir/ritonavir , Lopinavir/ritonavir (400/100 mg) BID + tenofovir DF + 1 NRTI. Baseline mg/dL (n=111 Number of patients with LDL-cholesterol measured. ) Week 48 mg/dL (n=75 ) Week 48 Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. (n=74 ) Baseline mg/dL (n=108 ) Week 48 mg/dL (n=76 ) Week 48 Change (n=73 ) LDL-Cholesterol Fasting. 108 98 -10% 104 103 +1% HDL-Cholesterol 40 39 -7% 39 41 +2% Total Cholesterol 188 170 -8% 181 187 +6% Triglycerides 215 161 -4% 196 224 +30% Adverse Reactions in Pediatric Patients: Atazanavir Capsules The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of atazanavir in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade 2 to 4 adverse events (≥5%, regardless of causality) reported in pediatric patients 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 patients. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric patients taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3 to 4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir DF-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients. In Study AI424-045, 20 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. In Studies AI424-008 and AI424-034, 74 patients treated with 400 mg of atazanavir once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the atazanavir-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of the atazanavir-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients [see Warnings and Precautions (5.8) ]. 6.2 Postmarketing Experience The following events have been identified during postmarketing use of atazanavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: edema Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1) ] Gastrointestinal System: pancreatitis Hepatic System: hepatic function abnormalities Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6) ] , cholecystitis, cholestasis Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9) ] Musculoskeletal System: arthralgia Renal System: nephrolithiasis [see Warnings and Precautions (5.6) ] , interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5) ] Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2) ] , pruritus, angioedema

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0E5TBG"> <caption>Table 7: Selected Adverse Reactions <footnote ID="_Ref523129715">Includes events of possible, probable, certain, or unknown relationship to treatment regimen.</footnote> of Moderate or Severe Intensity Reported in &#x2265;2% of Adult Treatment-Naive Patients, <footnote ID="_Ref523129728">Based on the regimen containing atazanavir.</footnote> Study AI424-138 </caption> <colgroup> <col width="33%"/> <col width="33%"/> <col width="33%"/> </colgroup> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">96 weeks</content> <footnote ID="_Ref523129742">Median time on therapy.</footnote> <content styleCode="bold">atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF with emtricitabine</content> <footnote ID="_Ref523129783">As a fixed-dose combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.</footnote> <content styleCode="bold">(n=441)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">96 weeks</content> <footnoteRef IDREF="_Ref523129742"/> <content styleCode="bold">lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir DF with emtricitabine</content> <footnoteRef IDREF="_Ref523129783"/> <content styleCode="bold">(n=437)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Digestive System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Jaundice/scleral icterus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and Appendages</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> ^* None reported in this treatment arm. </paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0EN1BG"> <caption>Table 8: Selected Adverse Reactions <footnote ID="_Ref523129967">Includes events of possible, probable, certain, or unknown relationship to treatment regimen. </footnote> of Moderate or Severe Intensity Reported in &#x2265;2% of Adult Treatment-Naive Patients, <footnote ID="_Ref523129987">Based on regimens containing atazanavir.</footnote> Studies AI424-034, AI424-007, and AI424-008 </caption> <colgroup> <col width="25%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> <col width="19%"/> </colgroup> <tbody> <tr> <td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Study AI424-034</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Studies AI424-007, -008</content> </paragraph> </td> </tr> <tr> <td align="center" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">64 weeks</content> <footnote ID="_Ref523130019">Median time on therapy.</footnote> <content styleCode="bold"> atazanavir 400 mg once daily + lamivudine + zidovudine</content> <footnote ID="_Ref523130093">As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.</footnote> <content styleCode="bold">(n=404)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">64 weeks</content> <footnoteRef IDREF="_Ref523130019"/> <content styleCode="bold"> efavirenz 600 mg once daily + lamivudine + zidovudine</content> <footnoteRef IDREF="_Ref523130093"/> <content styleCode="bold">(n=401)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">120 weeks</content> <footnoteRef IDREF="_Ref523130019"/> <content styleCode="bold"> ^, </content> <footnote ID="_Ref523130047">Includes long-term follow-up.</footnote> <content styleCode="bold">atazanavir 400 mg once daily + stavudine + lamivudine or didanosine</content> <content styleCode="bold">(n=279)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">73 weeks</content> <footnoteRef IDREF="_Ref523130019"/> <content styleCode="bold"> ^, </content> <footnoteRef IDREF="_Ref523130047"/> <content styleCode="bold">nelfinavir 750 mg TID or 1250 mg BID ⁺ stavudine + lamivudine or didanosine </content> <content styleCode="bold">(n=191)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Digestive System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Jaundice/scleral icterus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abdominal pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Peripheral neurologic symptoms</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and Appendages</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1%</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> ^* None reported in this treatment arm. </paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0E4LAI"> <caption>Table 9: Selected Adverse Reactions <footnote ID="_Ref523133348">Includes events of possible, probable, certain, or unknown relationship to treatment regimen.</footnote> of Moderate or Severe Intensity Reported in &#x2265;2% of Adult Treatment-Experienced Patients, <footnote ID="_Ref523133376">Based on the regimen containing atazanavir.</footnote> Study AI424-045 </caption> <colgroup> <col width="33%"/> <col width="33%"/> <col width="33%"/> </colgroup> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">48 weeks</content> <footnote ID="_Ref523133388">Median time on therapy.</footnote> <content styleCode="bold">atazanavir/ritonavir 300/100 mg once daily + tenofovir DF + NRTI</content> <content styleCode="bold">(n=119)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">48 weeks</content> <footnoteRef IDREF="_Ref523133388"/> <content styleCode="bold">lopinavir/ritonavir 400/100 mg twice daily</content> <footnote ID="_Ref523133411">As a fixed-dose combination.</footnote> <content styleCode="bold"> + tenofovir DF + NRTI</content> <content styleCode="bold">(n=118)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fever</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Digestive System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Jaundice/scleral icterus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Musculoskeletal System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Myalgia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>*</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> ^* None reported in this treatment arm. </paragraph> </td> </tr> </tbody> </table>