1 INDICATIONS AND USAGE REYATAZ ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg.

Limitations of Use: • REYATAZ is 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 REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4) ] .

REYATAZ is 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 3 months and older weighing at least 5 kg.

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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 Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 REYATAZ in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials.

536 participants received REYATAZ 300 mg with ritonavir 100 mg and 1089 participants received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive participants receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 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 * 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 REYATAZ.

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.

96 weeks c REYATAZ 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% 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 * None reported in this treatment arm.

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

b Based on regimens containing REYATAZ.

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.

Study AI424-034 Studies AI424-007, -008 64 weeks c REYATAZ 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 REYATAZ 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% Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ 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 REYATAZ 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 * 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 REYATAZ.

c Median time on therapy.

d As a fixed-dose product.

48 weeks c REYATAZ 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% * Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.

Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424-138 a Based on the regimen containing REYATAZ.

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.

96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d Variable Limit e (n=441) (n=437) Chemistry High SGOT/AST ≥5.1 × ULN 3% 1% SGPT/ALT ≥5.1 × ULN 3% 2% Total Bilirubin ≥2.6 × ULN 44% <1% Lipase ≥2.1 × ULN 2% 2% Creatine Kinase ≥5.1 × ULN 8% 7% Total Cholesterol ≥240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 * None reported in this treatment arm.

a Based on regimen(s) containing REYATAZ.

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.

Study AI424-034 Studies AI424-007, -008 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine Variable Limit d (n=404) (n=401) (n=279) (n=191) Chemistry High SGOT/AST ≥5.1 × ULN 2% 2% 7% 5% SGPT/ALT ≥5.1 × ULN 4% 3% 9% 7% Total Bilirubin ≥2.6 × ULN 35% <1% 47% 3% Amylase ≥2.1 × ULN * * 14% 10% Lipase ≥2.1 × ULN <1% 1% 4% 5% Creatine Kinase ≥5.1 × 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% 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 a REYATAZ 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 REYATAZ with ritonavir arm.

Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm.

Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm.

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.

REYATAZ with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL mg/dL Change d mg/dL Change d mg/dL mg/dL Change d mg/dL Change d (n=428 e ) (n=372 e ) (n=372 e ) (n=342 e ) (n=342 e ) (n=424 e ) (n=335 e ) (n=335 e ) (n=291 e ) (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% Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 a REYATAZ 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 REYATAZ arm.

Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ 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.

REYATAZ a,b efavirenz b,c Baseline mg/dL (n=383 e ) Week 48 mg/dL (n=283 e ) Week 48 Change d (n=272 e ) Baseline mg/dL (n=378 e ) Week 48 mg/dL (n=264 e ) Week 48 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% Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14.

Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045 a a Based on regimen(s) containing REYATAZ.

b Median time on therapy.

c ULN = upper limit of normal.

d As a fixed-dose product.

48 weeks b 48 weeks b REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI Variable Limit c (n=119) (n=118) Chemistry High SGOT/AST ≥5.1 × ULN 3% 3% SGPT/ALT ≥5.1 × ULN 4% 3% Total Bilirubin ≥2.6 × ULN 49% <1% Lipase ≥2.1 × ULN 5% 6% Creatine Kinase ≥5.1 × ULN 8% 8% Total Cholesterol ≥240 mg/dL 25% 26% Triglycerides ≥751 mg/dL 8% 12% Glucose ≥251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% 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 REYATAZ with ritonavir than with lopinavir/ritonavir.

However, the clinical impact of such findings has not been demonstrated.

Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 a REYATAZ 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 REYATAZ with ritonavir arm.

Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm.

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.

REYATAZ with ritonavir a,b Lopinavir/ritonavir b,c Baseline mg/dL (n=111 e ) Week 48 mg/dL (n=75 e ) Week 48 Change d (n=74 e ) Baseline mg/dL (n=108 e ) Week 48 mg/dL (n=76 e ) Week 48 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% Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ 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 REYATAZ 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 REYATAZ in adults.

The most common Grade 2–4 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 3–4 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 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Oral Powder The data described below reflect exposure to REYATAZ oral powder in 155 participants weighing at least 5 kg to less than 35 kg, including 134 participants exposed for 48 weeks.

These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric participants with HIV-1 (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]).

Age ranged from 3 months to 10 years of age.

In these studies, 51% were female and 49% were male.

All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules.

The most common Grade 3–4 laboratory abnormalities occurring in pediatric participants weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%).

All other Grade 3–4 laboratory abnormalities occurred with 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 REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir.

In Study AI424-045, 20 participants administered REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir.

In Studies AI424-008 and AI424-034, 74 participants treated with REYATAZ 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 REYATAZ, 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 REYATAZ, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir.

Within REYATAZ 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 REYATAZ.

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