ATAZANAVIR TEVA 200 mg

1 INDICATIONS AND USAGE Atazanavir capsule is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg. Limitations of Use: Atazanavir capsules are not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4) ]. Use of atazanavir capsules with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4) ] . Atazanavir capsule is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg. ( 1 )

2 DOSAGE AND ADMINISTRATION Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. ( 2.2 ) Treatment-naive adults: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food or atazanavir capsules 400 mg once daily with food. ( 2.3 ) Treatment-experienced adults: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food. ( 2.3 ) Pediatric patients: Atazanavir capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. ( 2.4 ) Pregnancy: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. ( 2.6 ) Dosing modifications: may be required for concomitant therapy ( 2.3 , 2.4 , 2.6 ), renal impairment ( 2.7 ), and hepatic impairment. ( 2.8 ) 2.1 Overview Atazanavir capsules must be taken with food. Do not open the capsules. The recommended oral dosage of atazanavir capsules depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2 -receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3 , 2.4 , and 2.6 ) and Drug Interactions (7) ] . Atazanavir capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) ] . Efficacy and safety of atazanavir capsules with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir. 2.2 Testing Prior to Initiation and During Treatment with Atazanavir Capsules Renal laboratory testing should be performed in all patients prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5 , 5.6) ]. Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules [see Warnings and Precautions (5.4) ]. 2.3 Dosage of Atazanavir Capsules in Adult Patients Table 1 displays the recommended dosage of atazanavir capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of atazanavir capsules and ritonavir when given concomitantly with other antiretroviral drugs and H 2 -receptor antagonists (H2RA). Ritonavir is required with several atazanavir capsules dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of atazanavir capsules in treatment-experienced adult patients without ritonavir is not recommended. Table 1: Recommended Atazanavir Capsules and Ritonavir Dosage in Adults a a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (e.g., H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (e.g., efavirenz, tenofovir DF, and didanosine). Atazanavir Capsules Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg 2.4 Dosage of Atazanavir Capsules in Pediatric Patients The recommended daily dosage of atazanavir capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2). Table 2: Recommended Dosage of Atazanavir Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age) a,b a Administer atazanavir capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (e.g., H2RA or PPIs), and other antiretroviral drugs (e.g., efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, atazanavir capsules must be administered with ritonavir. Body weight Atazanavir Capsules Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experienced c Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. 2.6 Dosage Adjustments in Pregnant Patients Table 4 includes the recommended dosage of atazanavir capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, atazanavir capsules must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended atazanavir capsules dosage in adults) [see Use in Specific Populations (8.1) ]. Table 4: Recommended Dosage of Atazanavir Capsules and Ritonavir in Pregnant Patients a a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (e.g., H2RA or PPIs), and other antiretroviral drugs (e.g., efavirenz, tenofovir DF, and didanosine). b Atazanavir capsules are not recommended for treatment-experienced pregnant patients during the second and third trimester taking atazanavir capsules with BOTH tenofovir DF and H2RA. Atazanavir Capsules Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF b In combination with EITHER H2RA OR tenofovir DF 400 mg 100 mg 2.7 Dosage in Patients with Renal Impairment For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for atazanavir capsules. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive atazanavir capsules 300 mg with ritonavir 100 mg. Atazanavir capsules are not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7) ]. 2.8 Dosage Adjustments in Patients with Hepatic Impairment Table 5 displays the recommended atazanavir capsules dosage in treatment-naive patients with hepatic impairment. The use of atazanavir capsules in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of atazanavir capsules with ritonavir in patients with any degree of hepatic impairment is not recommended. Table 5: Recommended Dosage of Atazanavir Capsules in Treatment-Naive Adults with Hepatic Impairment Atazanavir Capsules Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) Atazanavir capsules with or without ritonavir is not recommended

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 virus 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 patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of atazanavir in patients with progressive renal disease. ( 5.5 ) Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. ( 5.6 ) The concomitant use of atazanavir with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.7 , 7.3 ) Patients receiving atazanavir may develop new onset or exacerbations of diabetes mellitus/hyperglycemia ( 5.9 ), immune reconstitution syndrome ( 5.10 ), and redistribution/accumulation of body fat. ( 5.11 ) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. ( 5.12 ) 5.1 Cardiac Conduction Abnormalities Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10) ] . In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants who had on-study electrocardiogram measurements. Because of limited clinical experience in those 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 participants with HIV-1 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 virus or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with atazanavir and during treatment [see Dosage and Administration (2.2) , Adverse Reactions (6.1) , and Use in Specific Populations (8.8) ]. 5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with atazanavir and continued during treatment with atazanavir. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. In patients with progressive kidney disease, discontinuation of atazanavir may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2) ] . 5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 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 (virologic response) of atazanavir with ritonavir and possible development of resistance. See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7) ] . Consider the potential for drug interactions prior to and during therapy containing atazanavir with ritonavir; and monitor for the adverse reactions associated with 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 patients with HIV-1 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 , cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.11 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. 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) ] hyperbilirubinemia [see Warnings and Precautions (5.8) ] chronic kidney disease [see Warnings and Precautions (5.5) ] nephrolithiasis and cholelithiasis [ see Warnings and Precautions (5.6) ] Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 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 Participants The safety profile of atazanavir in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received atazanavir 300 mg with ritonavir 100 mg and 1089 participants 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 participants 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 a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424-138 96 weeks c atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/ emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d 400 mg/100 mg (twice daily) and tenofovir DF/ emtricitabine e (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. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing atazanavir. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeks c atazanavir 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d atazanavir 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and 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. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing atazanavir. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of atazanavir in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 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 participants receiving atazanavir with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, b Study AI424-045 48 weeks c Atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and 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. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing atazanavir. c Median time on therapy. d As a fixed-dose product. Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including atazanavir 300 mg with ritonavir 100 mg or 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 Participants with HIV-1, a Study AI424-138 Variable Limit e 96 weeks b atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c (n=441) 96 weeks b lopinavir/ritonavir 400 mg/100 mg c (twice daily) and tenofovir DF/emtricitabine d (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% a Based on the regimen containing atazanavir. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 Variable Limit d Study AI424-034 Studies AI424-007, -008 64 weeks b atazanavir 400 mg once daily and lamivudine/ zidovudine e (n=404) 64 weeks b efavirenz 600 mg once daily and lamivudine/ zidovudine e (n=401) 120 weeks b,c atazanavir 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine (n=279) 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and 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. a Based on regimen(s) containing atazanavir. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 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 with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL (n=428 e ) mg/dL (n=372 e ) Change d (n=372 e ) mg/dL (n=342 e ) Change d (n=342 e ) mg/dL (n=424 e ) mg/dL (n=335 e ) Change d (n=335 e ) mg/dL (n=291 e ) Change d (n=291 e ) LDL-Cholesterol f 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol f 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol f 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides f 126 145 +15% 140 +13% 129 194 +52% 184 +50% a Atazanavir 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants 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. e Number of participants with LDL-cholesterol measured. f Fasting. Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 atazanavir a,b efavirenz b,c Baseline Week 48 Week 48 Baseline Week 48 Week 48 mg/dL (n=383 e ) mg/dL (n=283 e ) Change d (n=272 e ) mg/dL (n=378 e ) mg/dL (n=264 e ) Change d (n=253 e ) LDL-Cholesterol f 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides f 138 124 -9% 129 168 +23% a Atazanavir 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. b 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. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including atazanavir with ritonavir having 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 Participants with HIV-1, Study AI424-045 a Variable Limit c 48 weeks b atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks b lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and 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% a Based on regimen(s) containing atazanavir. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with atazanavir with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 Atazanavir with ritonavir a,b Lopinavir/ritonavir b,c Baseline Week 48 Week 48 Baseline Week 48 Week 48 mg/dL (n=111 e ) mg/dL (n=75 e ) Change d (n=74 e ) mg/dL (n=108 e ) mg/dL (n=76 e ) Change d (n=73 e ) LDL-Cholesterol f 108 98 -10% 104 103 +1% HDL-Cholesterol 40 39 -7% 39 41 +2% Total Cholesterol 188 170 -8% 181 187 +6% Triglycerides f 215 161 -4% 196 224 +30% a Atazanavir 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. Adverse Reactions in Pediatric Participants with HIV-1: Atazanavir Capsules The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of atazanavir in pediatric participants with HIV-1 (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 participants 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 participants. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric participants 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 Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered atazanavir 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered atazanavir with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered atazanavir with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir. In Study AI424-045, 20 participants administered atazanavir 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered atazanavir with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered atazanavir with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 participants treated with atazanavir 400 mg 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 participants treated with atazanavir, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with atazanavir, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [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