Atazanavir (Page 4 of 12)

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:

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 Subjects

The safety profile of atazanavir in treatment-naive adults is based on 1,625 subjects with HIV-1 infection in clinical trials. 536 subjects received atazanavir 300 mg with ritonavir 100 mg and 1,089 subjects 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 subjects 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 Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive Subjects with HIV-1 Infectionb , Study AI424-138

96 weeksc

atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabined

(n=441)

96 weeksc

lopinavir/ritonavird 400 mg/100 mg (twice daily) and tenofovir DF/emtricitabinee

(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 Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive Subjects with HIV-1 Infectionb , Studies AI424-034, AI424-007, and AI424-008

Study AI424-034

Studies AI424-007, -008

64 weeksc

atazanavir 400 mg (once daily) with lamivudine/zidovudinee

(n=404)

64 weeksc

efavirenz 600 mg (once daily) with lamivudine/zidovudinee

(n=401)

120 weeksc,d

atazanavir 400 mg (once daily) with stavudine and lamivudine or didanosine

(n=279)

73 weeksc,d

nelfinavir 750 mg TID or 1,250 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 Subjects

The safety profile of atazanavir in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-experienced subjects receiving atazanavir with ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Experienced Subjects with HIV-1 Infectionb , Study AI424-045

48 weeksc atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119)

48 weeksc lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and NRTI

(n=118)

Body as 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 Subjects

The percentages of adult treatment-naive subjects with HIV-1 infection 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 Subjects with HIV-1 Infectiona , Study AI424-138

Variable

Limite

96 weeksb

atazanavir 300 mg with ritonavir

100 mg (once daily) and tenofovir DF/emtricitabinec

96 weeksb

lopinavir/ritonavir

400 mg/100 mgc

(twice daily) and tenofovir DF/emtricitabined

(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/mm3

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 a Treatment-Naive Subjects with HIV-1 Infectiona , Studies AI424-034, AI424-007, and AI424-008

Variable

Limitd

Study AI424-034

Studies AI424-007, -008

64 weeksb

atazanavir 400 mg once daily and lamivudine/zidovudinee

64 weeksb

efavirenz 600 mg once daily and lamivudine/zidovudinee

120 weeksb,c

atazanavir 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine

73 weeksb,c

nelfinavir 750 mg TID or 1,250 mg BID with stavudine and lamivudine or with stavudine and didanosine

(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/mm3

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 Subjects with HIV-1 Infection

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138

Atazanavir with ritonavira,b

Lopinavir/ritonavirb,c

Baseline

Week 48

Week 96

Baseline

Week 48

Week 96

mg/dL

mg/dL

Changed

mg/dL

Changed

mg/dL

mg/dL

Changed

mg/dL

Changed

(n=428e)

(n=372e)

(n=372e)

(n=342e)

(n=342e)

(n=424e)

(n=335e)

(n=335e)

(n=291e)

(n=291e)

LDL-Cholesterolf

92

105

+14%

105

+14%

93

111

+19%

110

+17%

HDL-Cholesterolf

37

46

+29%

44

+21%

36

48

+37%

46

+29%

Total Cholesterolf

149

169

+13%

169

+13%

150

187

+25%

186

+25%

Triglyceridesf

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-subject changes from baseline for subjects 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 subjects with LDL-cholesterol measured.

f Fasting.

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034

Atazanavira,b

Efavirenzb,c

Baseline

Week 48

Week 48

Baseline

Week 48

Week 48

mg/dL

mg/dL

Changed

mg/dL

mg/dL

Changed

(n=383e)

(n=283e)

(n=272e)

(n=378e)

(n=264e)

(n=253e)

LDL-Cholesterolf

98

98

+1%

98

114

+18%

HDL-Cholesterol

39

43

+13%

38

46

+24%

Total Cholesterol

164

168

+2%

162

195

+21%

Triglyceridesf

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-subject 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.

e Number of subjects with LDL-cholesterol measured.

f Fasting.

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection

The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including 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 Subjects with HIV-1 Infection, Study AI424-045a

48 weeksb

48 weeksb

Atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI

lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and NRTI

Variable

Limitc

(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/mm3

2%

3%

Neutrophils

<750 cells/mm3

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 Subjects with HIV-1 Infection

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with 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 ritonavira,b

Lopinavir/ritonavirb,c

Baseline

Week 48

Week 48

Baseline

Week 48

Week 48

mg/dL

mg/dL

Changed

mg/dL

mg/dL

Changed

(n=111e)

(n=75e)

(n=74e)

(n=108e)

(n=76e)

(n=73e)

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-subject changes from baseline for subjects with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.

e Number of subjects with LDL-cholesterol measured.

f Fasting.

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: Atazanavir Capsules

The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of atazanavir in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade 2 to 4 adverse events (≥ 5%, regardless of causality) reported in pediatric subjects were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in < 2% of subjects. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric subjects taking the capsule formulation were elevation of total bilirubin (≥ 3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3 to 4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 subjects administered atazanavir 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.

In Study AI424-045, 20 subjects administered atazanavir 300 mg with ritonavir 100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 25% (5/20) of the subjects administered atazanavir with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir-treated. AST levels > 5 times ULN developed in 10% (2/20) of the subjects administered atazanavir with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.

In Studies AI424-008 and AI424-034, 74 subjects 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 subjects treated with atazanavir, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels > 5 times ULN developed in 9% of the subjects treated with atazanavir, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions (5.8)].

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